PL193669B1 - Pharmaceutic compounds - Google Patents

Abstract

1. A compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) derivative of formula (I): wherein each X, which may be the same or different in a given molecule, is -CH= or -N=; each of R 1 to R 4 , which may be the same or different, is H, C 1 -C 4 -alkyl, OH, NH 2 , C 1 -C 4 -alkoxy, phenyl, phenyloxy, NHR , N(R)2 , wherein R is C1-C4-alkyl, CF3 or halogen; each of R5 and R6, which may be the same or different, is H or C1-C4-alkyl; Z stands for (CH 2 ) n , (CH 2 ) n O(CH 2 ) n , (CH 2 ) n N(R 7 )(CH 2 ) n , (CH 2 ) n N(R 7 )(CH 2 ) m N(R 7 )(CH 2 ) n or (CH 2 ) n N(CH 2 CH 2 ) 2 N(CH 2 ) n , (CH 2 ) n CONH(CH 2 ) m or (CH 2 ) n CONH (CH2)mNHCO(CH2)n, where R7 is H or C1-C4-alkyl and n and m, which may be the same or different, are integers 1 to 4; or a pharmaceutically acceptable acid addition salt thereof; except for compounds in which each X is N, each of R 1 to R 6 is H, the carboxamide moiety is bonded to position 1 of each phenazine ring and Z is (CH 2 ) 2 NH(CH 2 ) 2 , (CH 2 ) 3 NH(CH 2 ) 3 , (CH 2 ) 3 N(CH 2 CH 2 ) 2 N(CH 2 ) 3 , (CH 2 ) 2 NH- -(CH 2 ) 2 NH (CH 2 ) 2 or (CH 2 ) 3 NH(CH 2 ) 2 NH(CH 2 ) 3 . PL PL PL PL PL

Description

Description of the invention

The present invention relates to bis (acridinecarboxamide), bis (phenazinecarboxamide) compounds, a pharmaceutical composition containing them and their use.

Many compounds that bind reversibly to DNA by insertion are known to have antiproliferative properties of cells and in vivo antitumor activity, mediated mainly by their inhibition of topoisomerase enzymes. For example, acridine amsacrine derivatives [Issell, Cancer Treat. Rev. 1980, 7, 73], asulacrine [Harvey et al., Eur. J. Cancer, 1991, 27, 1617] and acridinecarboxamide [Finlay et al., Eur. J. Cancer 1996, 32A, 708] are clinical anti-cancer drugs or in clinical trials, and related 9-azaacridines (phenazines) have been shown to have anti-tumor properties in vivo in animal models [Rewcastle et al., J. Med. Chem., 1987, 30, 843].

It has now been found that a series of bis (acridinecarboxamide) and bis (9-phenazinecarboxamide) derivatives exhibit anti-tumor properties.

The present invention relates to a compound which is a bis (acridinecarboxamide) or a bis (phenazinecarboxamide) derivative of formula (I):

wherein each X, which may be the same or different on a given molecule, is -CH = or -N =; each of R1 to R4, which may be the same or different, is H, C1-C4-alkyl, OH, NH2, C1-C4-alkoxy, phenyl, phenyloxy, NHR, N (R) 2, where R is C1 -C4-alkyl, CF3, or halogen; each of R5 and R6, which may be the same or different, is H or C1-C4-alkyl; Z is (CH2) n, (CH2) nO (CH2) n, (CH2) nN (R7) (CH2) n, (CH2) nN (R7) (CH2) mN (R7) (CH2) n or (CH2) nN (CH2CH2) 2N (CH2) n, (CH2) nCONH (CH2) m or (CH2) nCONH (CH2) mNHCO (CH2) n, where R7 is H or C1-C4-alkyl and nim, which may be the same or different, represent integers from 1 to 4; or a pharmaceutically acceptable acid addition salt thereof; except for compounds where each X is N, each of R1 to R6 is H, the carboxamide moiety is linked to the 1-position of each phenazine ring and Z is (CH2) 2NH (CH2) 2, (CH2) 3NH (CH2 ) 3, (CH2) 3N (CH2CH2) 2N (CH2) 3, (CH2) 2-NH (CH2) 2NH (CH2) 2 or (CH2) 3NH (CH2) 2NH (CH2) 3.

In one aspect of the invention the compound is a bis (acridine carboxamide) derivative of formula (Ia):

wherein each of R1 and R3 that are the same or different is C1-C4-alkoxy, C1-C4-alkyl or halogen, each of R2 and R4 that are the same or different is hydrogen, C1-C4- alkoxy, C1-C4-alkyl or halogen and each of R5 and R6 is H; or a pharmaceutically acceptable salt thereof.

In another aspect of the invention the compound is a bis (phenazinecarboxamide) derivative of formula (Ib):

Wherein each of R1 and R3, which are the same or different, is C1-C4-alkoxy, C1-C4-alkyl or halogen, each of R2 and R4 that are the same or different is hydrogen, C1-C4-alkoxy, C1-C4-alkyl or halogen and each of R5 and R6 is H; or a pharmaceutically acceptable salt thereof.

The preferred compounds of the invention are:

bis [(7-ethylacridine-4-carboxamido) propyl] methylamine;

bis [(1-methylacridine-4-carboxamido) propyl] methylamine;

bis [(1-chloroacridine-4-carboxamido) propyl] methylamine;

bis [(2-methylacridine-4-carboxamido) propyl] methylamine;

bis [(2-chloroacridine-4-carboxamido) propyl] methylamine;

bis [(3-methylacridine-4-carboxamido) propyl] methylamine;

bis [(5-methylacridine-4-carboxamido) propyl] methylamine;

bis [(5-ethylacridine-4-carboxamido) propyl] methylamine;

bis [(5-isopropylacridine-4-carboxamido) propyl] methylamine;

bis [(5-phenylacridine-4-carboxamido) propyl] methylamine;

bis [(5-methoxyacridine-4-carboxamido) propyl] methylamine;

bis [(5-fluoroacridine-4-carboxamido) propyl] methylamine;

bis [(5-chloroacridine-4-carboxamido) propyl] methylamine;

bis [(5-bromoacridine-4-carboxamido) propyl] methylamine;

bis [(6-methoxyacridine-4-carboxamido) propyl] methylamine;

bis [(6-fluoroacridine-4-carboxamido) propyl] methylamine;

bis [(6-chloroacridine-4-carboxamido) propyl] methylamine;

bis [(7-methylacridine-4-carboxamido) propyl] methylamine;

bis [(7-isopropylacridine-4-carboxamido) propyl] methylamine;

bis [(7-tert-butylacridine-4-carboxamido) propyl] methylamine;

bis [(7-phenylacridine-4-carboxamido) propyl] methylamine;

bis [(7-methoxyacridine-4-carboxamido) propyl] methylamine;

bis [(7-fluoroacridine-4-carboxamido) propyl] methylamine;

bis [(7-chloroacridine-4-carboxamido) propyl] methylamine;

bis [(7-bromoacridine-4-carboxamido) propyl] methylamine;

bis [(8-methylacridine-4-carboxamido) propyl] methylamine;

bis [(8-chloroacridine-4-carboxamido) propyl] methylamine;

bis [(acridine-2-carboxamido) propyl] methylamine;

bis [(acridine-4-carboxamido) propyl] methylamine;

bis [2- (acridine-4-carboxamido) ethyl] amine;

bis [3- (acridine-4-carboxamido) propyl] amine;

N ¹ , N4-bis [(acridine-4-carboxamido) propyl] piperazine;

bis [(6-bromoacridine-4-carboxamido) propyl] methylamine;

bis [(5-trifluoromethylacridine-4-carboxamido) propyl] methylamine;

bis [(6-trifluoromethylacridine-4-carboxamido) propyl] methylamine;

bis [(5,7-dimethylacridine-4-carboxamido) propyl] methylamine;

bis [(6- (dimethylamino) acridine-4-carboxamido) propyl] methylamine;

bis [(phenazine-1-carboxamido) propyl] methylamine;

bis [(phenazine-2-carboxamido) propyl] methylamine;

bis [(6-methylphenazine-1-carboxamido) propyl] methylamine;

bis [(6-chlorophenazine-1-carboxamido) propyl] methylamine;

bis [(7-methylphenazine-1-carboxamido) propyl] methylamine;

bis [(7-methoxyphenazine-1-carboxamido) propyl] methylamine;

bis [(7-chlorophenazine-1-carboxamido) propyl] methylamine;

bis [(8-methylphenazine-1-carboxamido) propyl] methylamine;

bis [(8-methoxyphenazine-1-carboxamido) propyl] methylamine;

bis [(9-methylphenazine-1-carboxamido) propyl] methylamine;

bis [(9-methylphenazine-1-carboxamido) propyl] -1,4-piperazine;

bis [(9-methylphenazine-1-carboxamido) ethyl] -1,4-ethylenediamine;

bis [(9-methoxyphenazine-1-carboxamido) propyl] methylamine;

bis [(9-phenoxyphenazine-1-carboxamido) propyl] methylamine;

bis [(9-fluorophenazine-1-carboxamido) propyl] methylamine;

Bis [(9-chlorophenazine-1-carboxamido) propyl] methylamine; bis [((9-dimethylamino) phenazine-1-carboxamido) propyl] methylamine; bis [3- (5- (dimethylamino) acridine-4-carboxamido) propyl] methylamine; bis [3- (7- (dimethylamino) acridine-4-carboxamido) propyl] methylamine; bis [3- (5,8-dimethylacridine-4-carboxamido) propyl] methylamine;

bis [3- (1,5-dimethylacridine-4-carboxamido) propyl] methylamine;

bis [3- (8-chloro-5-methylacridine-4-carboxamido) propyl] methylamine;

bis [3- (1-chloro-5-methylacridine-4-carboxamido) propyl] methylamine;

bis [2- (3-methylphenazine-1-carboxamido) propyl] methylamine;

bis [(3-chlorophenazine-1-carboxamido) propyl] methylamine;

bis [3- (2-chlorophenazine-1-carboxamido) propyl] methylamine;

bis [3- (8-chlorophenazine-1-carboxamido) propyl] methylamine;

bis [3- (6,9-dimethylphenazine-1-carboxamido) propyl] methylamine;

bis [(6-chloro-9-methylphenazine-1-carboxamido) propyl] methylamine;

bis [(4-methylphenazine-1-carboxamido) propyl] methylamine;

bis [3- (9-methylphenazine-1-carboxamido) propyl] -1,2-ethylenediamine;

bis [2- (6-9-dimethylphenazine-1-carboxamido) ethyl] -1,2-ethylenediamine;

bis [2- (9-methylphenazine-1-carboxamido) propyl] -1,4-butanediamine;

bis [3- (5-methylacridine-4-carboxamido) ethyl] -1,2-ethylenediamine;

bis [3- (acridine-4-carboxamido) ethyl] -1,2-ethylenediamine;

bis [(9-methylphenazine-1-carboxamido) ethyl] -1,3-propanediamine;

bis [2- (6-chloro-9-methylphenazine-1-carboxamido) ethyl] -1,2-ethylenediamine;

N-1- {3 - [{3 - [(acridinyl-4-carbonyl) amino] propyl} (methyl) amino] propyl} phenazine-1-carboxamide;

N-1- {3 - [{3 - [(5-methylacridinyl-4-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide;

N-1- {3 - [{3 - [(phenazinyl-1-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide;

N-1- (2 - {[2 - ({2 - [(5-methylacridinyl-4-carbonyl) amino] ethyl} amino) ethyl] amino} ethyl) -9-methylphenazine-1-carboxamide; and

N-1- (2 - {[2 - ({2 - [(acridinyl-4-carbonyl) amino] ethyl} amino) ethyl] amino} ethyl) phenazine-1-carboxamide.

In formula (I), the ring numbering of each tricyclic chromophore differs depending on whether X is -CH = (acridine derivatives) or -N = (phenazine derivatives). The numbering used in each case, relative to one tricyclic moiety, is as follows:

In formula (I), the substituents R 1 and R 2, and R 3 and R 4, may occupy any of the available ring positions in their respective tricyclic chromophores. Thus, when X in the tricyclic moiety is -CH =, R1 and R2, or R3 and R4 as appropriate, may be linked to any of the available ring positions 1 to 8 not occupied by a -C carboxamide moiety (O ) -N (R5) -. The carboxamide moiety, in turn, may be attached to any ring position 1, 2, 3, and 4, preferably 1 or 4. Typically when X in a given tricyclic chromophore is -CH =, one of R1 and R2, or R3 and R4 as appropriate, is hydrogen and the other is hydrogen or is a substituent as defined above for formula (I) linked to any ring position 1 to 8 and the carboxamide moiety is attached to position 1 or 4.

When X in the tricyclic moiety is -N =, R1 and R2, or R3 and R4 as appropriate, may be bonded to any of the available ring positions 1 to 4 and 6 to 9 which are not occupied by a carboxamide moiety, in particular one of positions 6 to 9. The carboxamide moiety, in turn, may be linked to ring position 1 and 2, preferably 1. Typically, when X in a given tricyclic chromophore is -N =, one of R1 and R2, or R3 and R4 if appropriately, is hydrogen and the other is hydrogen or is a substituent as defined above for formula (I) linked to any position on the ring 1 to 4 or 6 to 9, particularly 6, 7, 8 or 9, and the carboxamide moiety is linked to the position 1 or 4.

When the left and right tricyclic chromophores in formula (I) are identical, the compounds are structurally symmetrical. When the two chromophores differ in the definition of one or more substituents, the compounds are structurally asymmetric. In a preferred aspect of the invention, the compounds are structurally symmetrical.

The C1-C4-alkyl group may be linear or branched, e.g. it may be methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl. The C1-C4-alkoxy group may similarly be linear or branched, e.g. it may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy or t-butoxy. Halogen is, for example, fluorine, chlorine, bromine or iodine.

Examples of specific compounds according to the invention are shown in the following Table I as their substitution pattern. All compounds are symmetrical, meaning that the left-handed tricyclic chromophore is identical to the right-handed. Thus, R1 = R3 and R2 = R4 in formula (I).

T a b e l a I

No R1 = R3 R2 = R4 X WITH 1 2 3 4 5 1 1-Me H. -CH = (CH2) 3NMe (CH2) 3 2 1-Cl H. -CH = (CH2) 3NMe (CH2) 3 3 2-Me H. -CH = (CH2) 3NMe (CH2) 3 4 2-Cl H. -CH = (CH2) 3NMe (CH2) 3 5 3-Me H. -CH = (CH2) 3NMe (CH2) 3 6 5-Me H. -CH = (CH2) 3NMe (CH2) 3 7 5-Et H. -CH = (CH2) 3NMe (CH2) 3 8 5-iPr H. -CH = (CH2) 3NMe (CH2) 3 9 5-Ph H. -CH = (CH2) 3NMe (CH2) 3 10 5-OMe H. -CH = (CH2) 3NMe (CH2) 3 11 5-F H. -CH = (CH2) 3NMe (CH2) 3 12 5-Cl H. -CH = (CH2) 3NMe (CH2) 3 13 5-Br H. -CH = (CH2) 3NMe (CH2) 3 14 5-CF3 H. -CH = (CH2) 3NMe (CH2) 3 15 6-OMe H. -CH = (CH2) 3NMe (CH2) 3 16 6-F H. -CH = (CH2) 3NMe (CH2) 3 17 6-Cl H. -CH = (CH2) 3NMe (CH2) 3 18 6-Br H. -CH = (CH2) 3NMe (CH2) 3

PL 193 669 B1 cont. table I.

1 2 3 4 5 19 6-CF3 H. -CH = (CH2) 3NMe (CH2) 3 twenty 6-NMe2 H. -CH = (CH2) 3NMe (CH2) 3 21 7-Me H. -CH = (CH2) 3NMe (CH2) 3 22 7-Et H. -CH = (CH2) 3NMe (CH2) 3 23 7-iPr H. -CH = (CH2) 3NMe (CH2) 3 24 7-tBu H. -CH = (CH2) 3NMe (CH2) 3 25 7-Ph H. -CH = (CH2) 3NMe (CH2) 3 26 7-OMe H. -CH = (CH2) 3NMe (CH2) 3 27 7-F H. -CH = (CH2) 3NMe (CH2) 3 28 7-Cl H. -CH = (CH2) 3NMe (CH2) 3 29 7-Br H. -CH = (CH2) 3NMe (CH2) 3 thirty 8-Me H. -CH = (CH2) 3NMe (CH2) 3 31 8-Cl H. -CH = (CH2) 3NMe (CH2) 3 32 5-Me 7-Me -CH = (CH2) 3NMe (CH2) 3 33 H. H. -CH = (CH2) 3NMe (CH2) 3 34 H. H. -CH = (CH2) 2NH (CH2) 3 35 H. H. -CH = (CH2) 3NH (CH2) 3 36 H. H. -CH = (CH2) 3NpipN (CH2) 3 # 37 H. H. -CH = (CH2) 3NMe (CH2) 3 38 H. H. -N = (CH2) 3NMe (CH2) 3 # 39 H. H. -N = (CH2) 3NMe (CH2) 3 40 6-Me H. -N = (CH2) 3NMe (CH2) 3 41 6-Cl H. -N = (CH2) 3NMe (CH2) 3 42 7-Me H. -N = (CH2) 3NMe (CH2) 3 43 7-OMe H. -N = (CH2) 3NMe (CH2) 3 44 7-Cl H. -N = (CH2) 3NMe (CH2) 3 45 8-Me H. -N = (CH2) 3NMe (CH2) 3 46 8-OMe H. -N = (CH2) 3NMe (CH2) 3 47 9-Me H. -N = (CH2) 3NMe (CH2) 3 48 9-Me H. -N = (CH2) 3NpipN (CH2) 3 49 9-Me H. -N = (CH2) 2NH (CH2) 2NH (CH2) 2 50 9-OMe H. -N = (CH2) 3NMe (CH2) 3 51 9-OPh H. -N = (CH2) 3NMe (CH2) 3 52 9-F H. -N = (CH2) 3NMe (CH2) 3 53 9-Cl H. -N = (CH2) 3NMe (CH2) 3 54 9-NMe2 H. -N = (CH2) 3NMe (CH2) 3 55 5-NMe2 H. -CH = (CH2) 3NMe (CH2) 3

PL 193 669 B1 cont. table I.

1 2 3 4 5 56 7-NMe ₂ H. -CH = (CH2) 3NMe (CH2) 3 57 5-Me 8-Me -CH = (CH2) 3NMe (CH2) 3 58 1-Me 5-Me -CH = (CH2) 3NMe (CH2) 3 59 8-Cl 5-Me -CH = (CH2) 3NMe (CH2) 3 60 1-Cl 5-Me -CH = (CH2) 3NMe (CH2) 3 61 3-Me H. -N = (CH2) 3NMe (CH2) 3 62 3-Cl H. -N = (CH2) 3NMe (CH2) 3 63 2-Cl H. -N = (CH2) 3NMe (CH2) 3 64 8-Cl H. -N = (CH2) 3NMe (CH2) 3 65 6-Me 9-Me -N = (CH2) 3NMe (CH2) 3 66 6-Cl 9-Me -N = (CH2) 3NMe (CH2) 3 67 4-Me H. -N = (CH2) 3NMe (CH2) 3 68 9-Me H. -N = (CH2) 3NH (CH2) 2NH (CH2) 3 69 6-Me 9-Me -N = (CH2) 2NH (CH2) 2NH (CH2) 2 70 9-Me H. -N = (CH2) 3NH (CH2) 2NH (CH2) 3 71 5-Me H. -CH = (CH2) 2NH (CH2) 2NH (CH2) 2 72 H. H. -CH = (CH2) 2NH (CH2) 2NH (CH2) 2 73 9-Me H. -N = (CH2) 2NH (CH2) 3NH (CH2) 2 74 6-Cl 9-Me -N = (CH2) 2NH (CH2) 2NH (CH2) 2 74a 9-Me H. -N = (CH2) 2NMe (CH2) 2NMe (CH2) 2

No a chromophore WITH a chromophore 75 acrydy n o-4-ka rbo ksya m id (CH2) 3NMe (CH2) 3 phenazine-1-carboxamide 76 5-methylacridine-4-carboxamide (CH2) 3NMe (CH2) 3 9-methylphenazine-1-carboxamide 77 phenazine-1-carboxamide (CH2) 3NMe (CH2) 3 9-methylphenazine-1-carboxamide 78 5-methylacridine-4-carboxamide (CH2) NH (CH2) 2NH (CH2) 2 9-methylphenazine-1-carboxamide 79 acrydy n o-4-ka rbo ksya m id (CH2) 2NH (CH2) 2NH (CH2) 2 phenazine-1-carboxamide

# represents the carboxamide at position 2 of acridine or phenazine. In all other cases, the carboxamide is at the 4-position of the acridines (X is -CH =) and the 1-position of the phenazines (X is -N =).

The invention also relates to a process for the preparation of a compound of formula I as defined above, characterized in that two moles of acridinecarboxylic acid or 9-azaacridine carboxylic acid derivative of formula (II) are reacted:

Wherein R1, R2 and X are as defined for formula I and A is OH, Cl or N-imidazolyl, with one mole of bis (amine) of formula (III):

NHR5-Z-NHR6 (III) wherein R5, R6 and Z are as defined for formula I and, if necessary, converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof. This coupling reaction is typically performed in a non-hydroxylic solvent, preferably THF. The reaction is conveniently carried out at a temperature from -10 ° C to 50 ° C.

The invention also relates to a pharmaceutical composition, comprising a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound of formula I as defined above.

According to the invention, the compound of formula I is for use as a medical agent in therapy, preferably as an anti-cancer agent.

The invention includes the use of a compound of Formula I in the manufacture of a medicament for the treatment of tumors.

The derivatives of formula (I) can be converted into pharmaceutically acceptable acid addition salts, and the salts can be converted into the free compound, by conventional methods. For example, acid addition salts can be prepared by contacting the free base with the appropriate amount of the desired acid in a conventional manner. Suitable salts include salts with organic and inorganic acids. Examples of suitable acids are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, methanesulfonic acid and the like. Depending on the structure and conditions, compounds can form multi-cationic forms.

Optional conversion of a compound of formula (I) into another compound of formula (I) may be carried out by conventional methods. For example, a fluoro group in a compound of formula can be substituted with an amino or thiol group to form an amine or thioether, respectively; a phenol or a thiol group in a compound of formula (I) may be alkylated to form an ether or thioether, respectively; an amino group can be acylated to give an N-acetate; and the nitro group can be reduced to form the amine. These are all routine transformations into organic chemistry.

The compounds of formula (I) may be converted to the corresponding N-oxide by conventional techniques, for example by dissolving them in CH2Cl2 and treating with 2- (phenylsulfonyl) -3-phenyloxaridine for 15 minutes to 24 hours, preferably for one hour, at a temperature of 0 ° C. to 60 °, preferably 20 ° C.

The free base form can be regenerated by treating the salt form with a base. The free base form differs from their corresponding salt forms in certain physical properties, but is otherwise equivalent to the corresponding free base form for the purposes of the invention.

Bis (amines) of general formula (III) are known compounds, and are either commercially available or prepared by methods described in the literature. Specific examples of such compounds are NH2 (CH2) 6NH2, NH2 (CH2) 3O (CH2) 3NH2, NH2 (CH2) 3NH (CH2) 3NH2, NH2 (CH2) 3NMe (CH2) 3NH2, NH2 (CH2) 2NH (CH2) 2NH - (CH2) 2NH2 and NH2 (CH2) 3N (CH2CH2) 2N (CH2) 3NH2.

The substituted acridinic acids of formula II wherein X is CH and A is OH can be prepared by the methods described in Atwell et al., J. Med. Chem., 1984, 27, 1481. This involves reduction of Al / Hg of the corresponding acridone-4-carboxylic acids of formula IV followed by reoxidation with FeCl3 or other suitable mild oxidant as shown in Scheme 1 below.

PL 193 669 B1

Scheme 1

The acridone-4-carboxylic acids of formula IV can in turn be prepared by a number of known methods, including the Jourdan-UlIman coupling of substituted anthranilic acids and halogen acids as described by Denny et al., J. Med. Chem., 1987, 30, 658, Jourdan-Uliman coupling of iodoisophthalic acid with substituted anilines as described by Rewcastle and Denny, Synthesis, 1985, 217, or by reaction of substituted diphenyliodonium carboxylates with substituted anilines as described by Rewcastle and Denny, Synthesis, 1985, 220, followed by cyclization of the resulting diphenylamine diacids and diphenylamine monoesters with PPA or PPE to form acridones. Reaction of acridine-4-carboxylic acids of formula II wherein A is OH with 1.1 equivalents of 1,1'-carbonyldiimidazole in DMF at 10-40 ° C for 10 minutes to 24 hours gives the corresponding imidazolide derivatives of compounds of formula II. They can be isolated by filtration and reacted with 0.5 equivalents of the bisamine of Formula III to provide the desired compounds of Formula I.

Certain of the substituted acridine-4-carboxylic acids of formula (II) and their derivatives are useful as intermediates in the preparation of compounds of general formula (I). Accordingly, the compound of formula (IIa):

wherein X, R1 and R2 are as defined for formula (I) and A is OH, Cl, N-imidazolyl or OR, where R is branched or unbranched, saturated or unsaturated C1-C6-alkyl, or aryl, except for unions in which:

(i) X is CH, A is OH, one of R1 and R2 is H and the other is H, Cl, OMe or Me and the -COA moiety is at position 4 of the tricyclic chromophore; and (ii) X is N, A is OH, one of R1 and R2 is H and the other is H, Cl, OMe or Me and the COA moiety is at position 1 of the tricyclic chromophore.

These compounds of formula (IIa) can be prepared by a process which is fully outlined in scheme 2 below. A method of producing a compound of formula (IIa) comprises cyclizing a compound of formula (X):

PL 193 669 B1

wherein R1 and R2 are as defined above. The cyclization is typically performed under acidic conditions, e.g. using neat trifluoroacetic acid for 12 hours at a temperature of 20 to 60 ° C.

Compounds of formula (X) are prepared as outlined in Scheme 2 below.

In Scheme 2, R1 and R2 are as defined above for general formula (I). The substituted diphenylamino acids (VII) are prepared by coupling the substituted anthranilic acids (V) with methyl (VI) 2-halobenzoates, typically iodobenzoate, and a copper catalyst in a polar solvent, typically butane-2,3-diol. It is described by Rewcastle and Denny, Synth. Comm., 1987, 17, 309. Reaction of substituted diphenylamic acids with 1,1'-carbonyldiimidazole (CDI) in a polar solvent, typically THF, gives imidazolides of formula (VIII) which are reduced in situ with an excess of metal based reducing agent. suitably sodium borohydride, to the alcohols of formula (IX).

Oxidation of the alcohols with solid MnO2 in a polar solvent, typically ethyl acetate or acetone, yields the corresponding aldehydes of formula (X) which is cyclized as indicated above to give substituted acridinium esters which are compounds of formula (II) wherein A is OMe. These esters can be hydrolyzed under acidic or basic conditions to the corresponding acids which are compounds of formula (II) wherein A is OH. These in turn can be activated by reaction with 1,1'-carbonyldiimidazole in a polar solvent (preferably dry DMF) to provide the corresponding imidazolide derivative which is a compound of formula (IIa) wherein A is N-imidazolyl, or by treatment with thionyl chloride in neutral in a solvent, typically dichloroethane, to give the corresponding acid chlorides which are compounds of formula (II) wherein A is Cl.

The latter intermediates can be coupled with the bis (amines) of formula (III) as described above to give the desired compounds of general formula (I). Alternatively, substituted acridinate esters of formula (II) where A = OMe can be reacted directly with bis (amines) of general formula III in a polar solvent, preferably ethanol or isopropanol, to provide compounds of general formula (I).

Phenazic acids, namely compounds of formula II in which X is N and A is OH, can be prepared by methods reported in the literature. Examples include J. Med. Chem. 1987, 30, 843;

PL 193 669 B1

Synth. Comm. 1987, 17, 1171; European patent application EP-A-172,744, and Chem. Abstr.

1986, 105, 97496p. They can then be converted into compounds of general formula I by the methods described above.

Further compounds of general formula (I) can also be prepared by the general method shown in scheme 3 below. In this approach, reaction of compounds of formula (II) (where A = imidazolide) with a mono-protected amine of formula (XI) gives an intermediate of formula (XII). Removal of the R8 protecting group gives the amines of formula (XIII) which can be coupled with another equivalent of a compound of formula (II) (where A = imidazolide) to provide compounds of formula (I). In Scheme 3, R1-R5, Z, and R6 are as defined above for formula (I), except that R7 may also be BOC, trityl, CO2CF3, or other suitable amine protecting group, and R8 is defined as BOC , trityl, CO2CF3, or other suitable amine protecting groups.

AND

Scheme 3

The compounds of formula (I) and their salts showed antitumor activity in biological tests.

The results are given in Example 78 below. The compounds have negligible toxicity and can therefore be used as anti-cancer agents. A human or animal patient having a tumor can thus be treated by a method comprising administering to him a compound of formula (I), or a salt or N-oxide thereof. The condition of the cancer patient may thus be improved. Examples of cancers in which compounds of formula (I) can be used to treat include lung and colon cancers, melanoma, and central nervous system (CNS) cancers.

The present compounds can be administered in a variety of dosage forms, e.g. orally, such as in the form of tablets, capsules, sugar-coated or film-coated tablets, liquid solutions or suspensions, or parenterally, e.g. intramuscularly, intramuscularly or subcutaneously. The present compounds may therefore be administered by injection or infusion.

PL 193 669 B1

The dosage depends on a number of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult is 50 mg / m ² to 5 g / m ^2. Such a dose may be administered, e.g., up to 5 times daily by injection, e.g. 3 times daily, infused over several hours, e.g. 3 hours, and / or by repeated administration.

The present compounds of formula (I) and their salts are formulated for use as a pharmaceutical or veterinary composition. The present invention therefore further provides a pharmaceutical or veterinary composition which comprises a pharmaceutically or veterinarily acceptable carrier or diluent and, as an active ingredient, a compound of formula (I) or a salt thereof. The compositions are typically prepared by conventional means and administered in a pharmaceutically or veterinarily suitable form.

For example, solid oral forms may contain, with the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binders such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates, or sodium starch glycolate; foaming mixtures, dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates. Such preparations may be manufactured in known manner, e.g. by mixing, granulating, tabletting, sugar-coating or other coatings.

The liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol. In particular, a syrup may contain as carrier, e.g., sucrose or sucrose with glycerin and / or mannitol and / or sorbitol. In particular, a diabetic syrup may contain as carriers only products, e.g. sorbitol, which do not metabolize to glucose or which metabolize only very little to glucose. Suspensions and emulsions may contain, as a carrier, for example a natural gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if necessary, a suitable amount of lidocaine hydrochloride. Typically compounds of formula (I) are formulated as aqueous solutions of the hydrochloride or other pharmaceutically acceptable salts. Solutions for intravenous injection or infusion may contain a carrier, e.g., sterile water, which is usually water for injection.

The invention is described below in the following examples with reference to the accompanying drawings in which:

Figure 1 is a plot of tumor volume in mm ³ (y axis) versus time in days (x axis) for growth retardation of colon tumor cells ??38 in the in vivo mouse assay as described in Example 80 below.

Example 1. Preparation of compound 22 of Table I by the method of Scheme 1. A mixture of 2-iodoisophthalic acid (2.92 g, 10 mmol), 4-ethylaniline (1.82 g, 15 mmol), CuCl (1 g) , 2,3-butanediol (12 ml) and benzene (10 ml) were heated and stirred allowing the benzene to evaporate. When the internal temperature of the reaction mixture reached 100 ° C, N-ethylmorpholine (6 ml) was added and the reaction mixture was stirred for an additional 4 hours at 120 ° C. The reaction mixture was then diluted with 0.5 M NH 4 OH (50 mL), treated with activated carbon and filtered through Celite. Acidification with 2M HCl gave a precipitate which was extracted into EtOAc (2x 100 mL), filtered through Celite and then extracted with 0.5M NH3 (100 mL). Acidification with concentrated HCl and recrystallization of the isolated product gave 2 - [(4-ethyl) phenylamino] isophthalic acid (2.36 g, 83%), mp (EtOAc / petroleum ether) 194.0-195.4 ° C.

¹ H NMR [(CD3) 2 SO] δ 1.15 (t, J = 7.6, 3H, CH 3), 2.51 (q, J = 7.6 Hz, 2 H, CH 2), 6.84 (d, J = 8.4 Hz, 2 H, H-2 'and H-6' or H-3 'and H-5'), 6.97 (t, J - 7.7 Hz, 1H, H-5), 7.04 (d, J = 8.4 Hz, 2 H, H-3 'and H-5' or H-2 'and H-6'), 7.92 (d, J = 7.6 Hz, 2 H, H-4 and H-6), 9.65 (br s, 1H, NH) and 12.90 (br s, 2H, 2x COOH). Analysis (C16H14NO4) C, H, N.

Reaction of the above diacid (1.43 g, 5 mmol) with polyphosphoric acid (38 g) was achieved by heating the mixture at 120 ° C for 2 hours. The cooled mixture was poured into boiling water (250 ml) to give a suspension of yellow solid. The precipitate was removed by filtration and dissolved in a mixture of MeOH (100 ml) and 1M NaOH (100 ml) which was heated and then filtered hot. Acidification of this mixture with glacial acetic acid gave yellow

A solid which was recrystallized to give 7-ethyl-9-oxoacridane-4-carboxylic acid (1.14 g, 89%), m.p. (H20) 301 ° C (decomposition).

¹ H NMR [(CD3) 2 SO] δ 1.26 (t, J = 7.6 Hz, 3 H, CH3), 2.74 (q, J = 7.6 Hz, 2 H, CH 2) 7, 33 (t, J = 7.7Hz, 1H, H-2), 7.64 (dd, J = 8.5, 2.1Hz, 1H, H-6), 7.71 (d, J = 8.5 Hz, 1H, H-5), 8.04 (br s, 1H, H-8), 8.42 (dd, J = 7.5, 1.7Hz, 1H, H-3), 8.52 (dd, J = 8.0, 1.7 Hz, 1H, H-1), 11.98 (s, 1H, NH), and 13.85 (br s, 1 H, COOH). Analysis (C16H13NO3) C, H, N.

A suspension of the above acridonic acid (1.00 g, 3.75 mmol) in 50% aqueous EtOH solution was stirred and heated, then sufficient triethylamine was added to form a clear yellow solution. Aluminum foil pieces (0.83 g) were amalgamated in a solution of HgCl2 (3 g) in EtOH, then added to the above vigorous boiling solution over 30 minutes. After completion of the reaction by tlc analysis, the reaction mixture was filtered and the solids collected, washed with a solution of KOH in aq. EtOH. The filtrate was then strongly acidified with concentrated HCl and treated with FeCl3 under reflux for 45 minutes. The reaction mixture was concentrated under reduced pressure and a sufficient amount of potassium acetate was added until the pH was neutral. Crystallization of the product occurred on cooling, and filtration and recrystallization of the resulting brown solid gave 7-ethylacridine-4-carboxylic acid (0.77 g, 82%), m.p. (acetone) 210-211.5 ° C.

¹ H NMR [(CD3) 2 SO] δ 1.35 (t, J = 7.5 Hz, 3 H, CH3), 2.91 (q, J = 7.5 Hz, 2 H, CH 2) 7, 83 (dd, J = 8.3, 7.2 Hz, 1H, H-2), 7.97 (dd, J = 9.0, 1.9 Hz, 1H, H-6), 8, 09 (br s, 1H, H-8), 8.26 (d, J = 9.0 Hz, 1H, H-5), 8.54 (dd, J = 8.4, 1.2 Hz , 1H, H-1), 8.71 (br d, J = 7.0Hz, 1H, H-3), 9.43 (s, 1H, H-9), 17.09 (br s, 1H, COOH). Analysis (C16H13NO2) C, H, N.

The above acridic acid (0.30 g, 1.2 mmol) was reacted with CDI (0.38 g, 2.39 mmol) in dry DMF (50 mL) for 4 hours at 50 ° C. DMF removed this under reduced pressure and the resulting oil was dissolved in a mixture of petroleum ether and CH2Cl2 (20 mL, 3: 1). Upon cooling, the imidazolide crystallized out and the crude material was used in the following coupling reaction. Coupling was done by dissolving 3,3'-diamino-N-methyldipropylamine (0.09 g) in THF (50 ml), cooling to 0 ° C (ice / water), and adding crude imidazolide in portions. The reaction mixture was allowed to stir overnight at room temperature, the THF was removed and the residue was diluted with CH2Cl2 (100 ml) and washed with 1M Na2CO3 (50 ml). The CH2Cl2 layer was dried with Na2SO4, the solvent was removed in vacuo and the resulting brown oil was purified by alumina chromatography (0.5% MeOH in CH2Cl2 as eluant) to afford bis [(7-ethylacridine-4-carboxamido) propyl] methylamine (22 ) (0.17 g, 47%) as yellow oil.

¹ H NMR (CDCl3) δ 1.28 (t, J = 7.5 Hz, 6 H, 2xCH3), 2.03-2.11 (m, 4 H, 2xCH2CH2CH2), 2.40 (s, 3 H , NCH3), 2.70 (q, J = 7.6 Hz, 4H, 2xCH2CH3), 2.79 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.74 (q, J = 6.2Hz, 4H, 2xCH2NH), 7.46 (br s, 2H, H-8), 7.48 (dd, J = 8.9, 1.8Hz, 2H, H-6) , 7.56 (dd, J = 8.3, 7.2Hz, 2H, H-2), 7.89 (d, J = 8.8Hz, 2H, H-5), 7.98 (dd, J = 8.3, 1.5 Hz, 2H, H-1), 8.51 (s, 2H, H-9), 8.86 (dd, J = 7.1, 1, 5 Hz, 2H, H-3), 11.80 (br t, J = 5.0 Hz, 2H, CONH).

HRMS (FAB ⁺ ) m / z calcd for C39H42N5O2 612.3339 (MH ⁺ ), found 612.3333.

Example 2: Preparation of Compound 1 of Table I by the Method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] of 1-methylacridine-4-carboxylic acid gave bis [(1-methylacridine-4-carboxamido) propyl] methylamine (1) as a yellow oil (91%).

¹ H NMR (CDCl3) δ 2.02-2.09 (m, 4 H, 2xCH2CH2CH2), 2.38 (s, 3 H, NCH 3), 2.75 (t, J = 7.5 Hz, 4 H , 2xCH2NCH3), 2.80 (d, J = 0.7Hz, 6H, 2CH3), 3.73 (q, J = 6.1Hz, 4H, 2xCH2NH), 7.36 (ddd, J = 8.2, 6.7, 0.9Hz, 2H, H-6 or H-7), 7.43 (dd, J = 7.6, 0.8Hz, 2H, H-2), 7.66 (ddd, J = 8.7, 6.7, 1.4 Hz, 2 H, H-7 or H-6), 7.80 (d, J = 8.0 Hz, 2 H, H -5 or H-8), 7.99 (dd, J = 8.7, 0.8 Hz, 2H, H-8 or H-5), 8.78 (s, 2H, H-9) , 8.80 (d, J = 7.3Hz, 2H, H-3) and 11.77 (br t, J = 5.1Hz, 2H, 2NH).

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O2 584.3026 (MH ⁺ ), found 584.3041. Analysis (C ₃₇ H ₃₇ N ₅ O ₂ O, 5H ₂ O) c, h, n.

Example 3: Preparation of Compound 2 in Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] of 1-chloroacridine-4-carboxylic acid gave bis [(1-chloroacridine-4-carboxamido) -propyl] methylamine (2) (83%), m.p. (CH2Cl2 / n-hexane) 94-96 ° C.

¹ H NMR (CDCl3) δ 2.02-2.09 (m, 4 H, 2xCH2CH2CH2), 2.39 (s, 3 H, NCH3), 2.79 (t, J = 7.4 Hz, 4 H , 2xCH2NCH3), 3.72 (q, J = 6.1Hz, 4H, 2xCH2NH), 7.31 (ddd, J = 8.2, 6.7, 0.8Hz, 2H, H-6 or

H-7), 7.63 (ddd, J = 8.7, 6.7, 1.3 Hz, 2 H, H-7 or H-6), 7.67 (d, J = 7.9 Hz , 2H, H-2), 7.74 (br d,

PL 193 669 B1

J = 8.0 Hz, 2H, H-5 or H-8), 7.91 (br d, J = 8.7 Hz, 2H, H-8 or H-5), 8.75 (d , J = 8.0 Hz, 2H, H-3),

8.98 (s, 2H, H-9), 11.45 (br t, J = 4.8Hz, 2H, 2xCONH).

HRMS (FAB ⁺⁾ m / z calcd for C35H32 Cl2N5O2 ³⁵ 624.1933 (MH ^+), found 624.1935 Analysis (C35H31Cl2N5O2) C, H, N.

Example 4: Preparation of Compound 3 of Table I by the Method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] of 2-methylacridine-4-carboxylic acid gave bis [(2-methylacridine-4-carboxamido) propyl] methylamine (3) as a yellow oil (90%).

¹ H NMR (CDCl3) δ 2.01-2.08 (m, 4 H, 2xCH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.60 (s, 3 H, 2xCH3), 2.73 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.70-3.77 (m, 4H, 2CH2NH), 7.38 (br t, J = 7.8Hz, 2H, H -6 or H-7), 7.64 (ddd, J = 8.6, 6.9, 1.5 Hz, 2H, H-7 or H-6), 7.76 (br s, 2H , H-1), 7.79 (d, J = 8.3 Hz, 2H, H-5 or H-8), 8.00 (d, J = 8.2 Hz, 2H, H-8 or H-5), 8.55 (s, 2 H, H-9), 8.76 (d, J = 2.2 Hz, 2 H, H-3), and 11.79 (br t, J = 5 (0 Hz, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O2 584.3026 (MH ⁺ ), found 584.3031. Analysis (C37H37N5O2) C, H, N.

Example 5: Preparation of Compound 4 of Table I by the Method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 2-chloroacridine-4-carboxylic acid gave bis [2-chloroacridine-4-carboxamido) propyl] methylamine (4) as a yellow solid (54%), m.p. (CH2Cl2 / n-hexane) 175.5-176.5 ° C.

¹ H NMR (CDCl3) δ 2.00-2.07 (m, 4H, 2xCH2CH2CH2), 2.38 (s, 3H, NCH3), 2.75 (t, J = 7.4 Hz, 4H, 2xCH2NCH3) , 3.71 (q, J = 6.2 Hz, 4H, 2xCH2NH), 7.42 (ddd, J = 8.3, 6.6, 0.9Hz, 2H, H-6 or H-7) , 7.68 (ddd, J = 8.7, 6.6, 1.3 Hz, 2H, H-7 or H-6), 7.74 (br d, J = 7.9 Hz, 2H, H -5 or H-8), 7.93-7.96 (m, 4H, H-1 and H-8 or H-5), 8.49 (s, 2H, H-9), 8.74 ( d, J = 2.5 Hz, 2H, H-3) and 11.52 (br t, J = 5.0 Hz, 2xNH).

HRMS (FAB ⁺⁾ m / z calcd for C35H32 Cl2N5O2 ³⁵ 624.1993 (MH ^+), found 624.1900. Analysis (C35H38N5O2) C, H, N.

Example 6: Preparation of Compound 5 of Table I by the Method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 3-methylacridine-4-carboxylic acid followed by purification on alumina followed by silica gel chromatography gave bis [(3-methylacridone-4-carboxamido) propyl] methylamine (5) as a pale yellow resin (15 %).

¹ H NMR (CDCl3) δ 1.78-1.84 (m, 4 H, 2xCH2CH2CH2), 2.18 (s, 3 H, NCH 3), 2.48 (s, 6 H, 2xCH3), 2.67 (t, J = 6.5Hz, 4H, 2xCH2NCH3), 3.56 (q, J = 6.1Hz, 4H, 2xCH2NH), 7.19 (d, J = 8.6Hz, 2H , H-1 or H-2), 7.33 (ddd, J = 8.4, 6.6, 1.0 Hz, 2H, H-6 or H-7), 7.39 (br t, J = 5.3 Hz, 2H, 2xNH), 7.58 (ddd, J = 8.8, 6.6, 1.4 Hz, 2H, H-7 or H-6), 7.66 (d , J = 8.7 Hz, H-2 or H-1), 7.70 (br d, J = 7.9 Hz, 2 H, H-5 or H-8), 7.94 (d, J = 8.6 Hz, 2H, H-8 or H-5) and 8.37 (s, 2H, H-9).

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O2 584.3026 (MH ⁺ ), found 584.3016.

Example 7: Preparation of Compound 6 of Table I by the Method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 5-methylacridine-4-carboxylic acid gave bis [(5-methylacridine-4-carboxamido) propyl] methylamine (6) (530) as a yellow oil.

¹ H NMR (CDCl3) δ 1.61 (s, 6 H, 2xCH3), 1.97-2.00 (m, 4 H, 2xCH2CH2CH2), 2.30 (s, 3 H, NCH 3), 2.58 (t, J = 7.5 Hz, 4 H, 2xCH2NCH3), 3.70 (q, J = 6.5 Hz, 4H, 2xCH2NH), 7.37 (dd, J = 8.5, 6.8 Hz, 2H, H-7), 7.57 (br d, J = 6.7 Hz, 2 H, H-8), 7.61 (dd, J = 8.3, 7.2 Hz, 2 H, H-2), 7.74 (br d, J = 8.6 Hz, 2 H, H-6), 8.03 (dd, J = 8.4, 1.5 Hz, 2 H, H -1), 8.69 (s, 2 H, H-9), 8.94 (dd, J = 7.1, 1.5 Hz, 2 H, H-3), 11.79 (br t, J = 5.1 Hz, 2H, 2xNH).

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O2 584.3026 (MH ⁺ ), found 584.3044.

Example 8: Preparation of compound 7 of Table I by the method of Scheme 1. A similar reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-ethyl-9-oxoacridine-4-carboxylic acid as above gave 5-ethylacridine acid -4-carboxylic acid (790), m.p. (acetone) 239-240.5 ° C.

¹ H NMR [(CD3) 2 SO] δ 1.43 (t, J = 7.5 Hz, 3 H, CH3), 3.27-3.38 (m, 2 H, CH2 - obscured by H 2 O) 7 , 73 (br t, J = 7.2 Hz, 1H, H -2), 7.87 (br t, J = 7.8 Hz, 1H, H-7), 7.93 (br d, J = 6.6 Hz, 1H, H-1), 8.19 (br d, J = 8.4 Hz, 1H, H-6), 8.57 (br d, J = 8.2 Hz , 1H, H-8), 8.76 (br d, J = 6.9Hz, 1H, H-3), 9.54 (s, 1H, H-9), and 17.44 (br s, 1, COOH). Analysis (C16H13NO2) C, H, N.

Product activation and coupling as above gave bis [(5-ethylacridine-4-carboxamido) propyl] methylamine (7) (570) as a yellow oil.

GB ¹ 193 669 B1 H NMR [CDCl3] δ 1.42 (t, J = 7.5 Hz, 6 H, 2xCH3), 1.97-2.04 (m, 4 H, 2xCH2CH2CH2), 2.32 ( s,

H, NCH3), 2.61 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.24 (q, J = 7.5Hz, 4H, 2xCH2CH3), 3.69 (q,

J = 6.2Hz, 4H, 2xCH2NH), 7.40 (dd, J = 8.4, 6.8Hz, 2H, H-7), 7.53 (dd, J = 6.7Hz , 1.0, 2H, H-6),

7.60 (dd, J = 8.3, 7.1 Hz, 2H, H-2), 7.74 (dd, J = 8.2, 1.0 Hz, 2H, H-8), 8.02 (dd, J = 8.4, 1.5Hz, 2H,

H-1), 8.69 (s, 2 H, H-9), 8.93 (dd, J = 7.1, 1.6 Hz, 2 H, H-3), and 11.77 (br t , J = 5.5 Hz, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C39H42N5O2 612.3339 (MH ⁺ ), found 612.3343.

Example 9: Preparation of compound 8 of Table I by the method of Scheme 1. A similar reaction of 2-iodoisophthalic acid and 2-isopropylaniline gave 2 - [(2-isopropyl) phenylamino] -isophthalic acid (38%), melting point (EtOAc (petroleum ether) 217-219 ° C.

¹ H NMR [(CD3) 2 SO] δ 1.25 (d, J = 6, 8 Hz, 6 H, 2xCH3), 3,22-3,29 (m, 1H, CH), 6.81 (dd , J = 7.4, 1.8 Hz, 1H, H-3 'or H-6'), 6.93 (t, J = 7.7Hz, 1H, H-2), 6.92 -7.02 (m, 2 H, H-4 'and H-5'), 7.26 (dd, J = 7.1, 2.2 Hz, 1H, H-6 'or H-3' ), 7.90 (d, J = 7.7Hz, 2H, H-4 and H-6), 9.69 (s, 1H, NH), 12.93 (br s, 2H, 2xCOOH ). Analysis of (C17H17NO4) C, H, N.

Cyclization of the product as above gave 5-isopropyl-9-oxoacridane-4-carboxylic acid (91%), mp (H20) 304 ° C (decomposition).

¹ H NMR [(CD3) 2 SO] δ 1.42 (d, J = 6.8 Hz, 6 H, 2xCH3), 3,29-3,41 (m, 1H, CH), 7,31-7 , 40 (m, 2H, H-2 and H-7), 7.74 (dd, J = 7.4, 1.2Hz, 1H, H-6), 8.15 (dd, J = 8.1, 1.2Hz, 1H, H-8), 8.47 (dd,

J = 7.6, 1.6 Hz, 1H, H-3), 8.53 (dd, J = 8.0, 1.6 Hz, 1H, H-1), 12.48 (s, 1H, NH), 14.07 (br s, 1H,

COOH). Analysis (Ο ₁₇ Η ₁₅ ΝΟ ₃ · 0.25 H ₂ O). C, H, N.

Reduction of the product as above gave 5-isopropylacridine-4-carboxylic acid (70%), m.p. (acetone) 238 ° C (decomposition).

¹ H NMR [(CD3) 2 SO] δ 1.45 (d, J = 6.8 Hz, 6 H, 2xCH3), 3,94-4,05 (m, 1H, CH), 7.75 (dd , J = 8.4, 7.1 Hz, 1H, H-2 or H-7), 7.86 (dd, J = 8.4, 7.1 Hz, 1H, H-7 or H- 2), 7.95 (br d, J = 6.9 Hz, 1H, H-6), 8.18 (dd, J = 8.4, 1.0 Hz, 1H, H-8), 8.55 (dd, J = 8.4, 1.4 Hz, 1H, H-1), 8.75 (dd, J = 7.1, 1.4 Hz, 1H, H-3), 9.52 (s, 1H, H-9), 17.39 (br s, 1H, COOH). Analysis (C17H15NO2) C, H, N.

Product activation and cyclization as above gave bis [(5-isopropylacridine-4-carboxamido) propyl] methylamine (8) (70%) as a foam.

¹ H NMR (CDCl3) δ 1.47 (d, J = 7.0 Hz, 12 H, 4xCH3), 1,96-2,03 (m, 4 H, 2xCH2CH2CH2), 2.32 (s, 3 H , NCH3), 2.59 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.70 (q, J = 7.1, 6.3Hz, 4H, 2xCH2NH), 4.154.18 ( m, 2H, 2xCH), 7.53 (dd, J = 8.4, 6.9Hz, 2H, H-7), 7.63 (dd, J = 8.3, 7.2Hz, 2 H, H-2), 7.67 (br d, J = 6.6 Hz, 2 H, H-6), 7.83 (dd, J = 8.4, 1.1 Hz, 2 H, H-8), 8.07 (dd, J = 8.3, 1.5 Hz, 2 H, H-1), 8.80 (s, 2 H, H-9), 8.95 (dd, J = 7.1, 1.6 Hz, 2H, H-3), 11.80 (br t, J = 5.6 Hz, 2NH).

HRMS (FAB ⁺ ) m / z calcd for C41H46N5O2 640.3652 (MH ⁺ ), found 640.3657. Analysis (C41H45N5O2) C, H, N.

Example 10: Preparation of compound 9 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 5-phenylacridine-4-carboxylic acid gave bis [(5-phenylacridine-4-carboxamido) propyl] methylamine (9) (64%) as yellow oil.

¹ H NMR (CDCl3) δ 1.24-1.26 (m, 4 H, 2xCH2CH2CH2), 2.04 (s, 3 H, NCH 3), 2,06-2,10 (br t, J = 7. 7 Hz, 4H, 2xCH2NCH3), 3.13 (q, J = 7.0, 6.7 Hz, 4H, 2xCH2NH), 7.43-7.45 (m, 2H, H-4 ') , 7.497.53 (m, 4 H, H-3 'and H-5'), 7.59-7.67 (m, 8 H, H-2, H-2 ', H6', H-7) , 7.75 (dd, J = 6.7, 1.4Hz, 2H, H-6), 7.99 (dd, J = 8.5, 1.3Hz, 2H, H-8) , 8.09 (dd, J = 8.4, 1.5Hz, 2H, H-1), 8.88 (s, 2H, H-9), 8.94 (dd, J = 7, 2.1.5 Hz, 2H, H-3), 11.06 (br t, J = 6.0 Hz, 2NH).

HRMS (FAB ⁺ ) m / z calcd for C47H42N5O2 708.3339 (MH ⁺ ), found 708.3345.

Example 11: Preparation of compound 10 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem., 1987, 30, 664] of 5-methoxyacridine-4-carboxylic acid gave bis [(5-methoxyacridine-4-carboxamido) propyl] methylamine (10) (71%) as a yellow oil.

¹ H NMR (CDCl3) δ 1,99-2, 06 (m, 4 H, 2xCH2CH2CH2), 2.38 (s, 3 H, NCH3), 2.72 (t, J = 7.6 Hz, 4 H , 2xCH2NCH3), 3.65 (q, J = 7.0, 5.2 Hz, 4H, 2xCH2NH), 3.87 (s, 6H, 2xOCH3), 6.67 (dd, J = 6.5 , 2.0Hz, 2H, H-6), 7.10-7.16 (m, 4H, H-7 and H-8), 7.54 (dd, J = 8.2, 7, 2 Hz, 2 H, H-2), 7.86 (dd, J = 8.4, 1.3 Hz, 2 H, H-1), 8.36 (s, 2 H, H-9), 8.82 (dd, J = 7.1, 1.5 Hz, 2H, H-3), 12.04 (br t, J = 4.6 Hz, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O4 616.2924 (MH ⁺ ), found 616.2943.

Example 12: Preparation of compound 11 from Table I by the method of Scheme 1. Reduction of the known [Rewcastle and Denny, Synthesis, 1965, 217] of 5-fluoro-9-oxoacridane-4-carboxy16

GB 193 669 B1 ester as above gave 5-fluoroakrydyno-4-carboxylic acid (90%), mp (MeOH / H2 O) 295-298 ° C (dec), ¹ H NMR [(CD3) 2 SO] δ 7.74 -7.80 (m, 1H, ArH), 7.90-7.96 (m, 2H, ArH), 8.19 (d, J = 8.6Hz, 1H,

ArH), 8.61 (dd, J = 8.6, 1.2 Hz, 1H, ArH), 8.81 (dd, J = 7.0, 1.0 Hz, 1H, ArH), 9 . 65 (s, 1H, H-9). Analysis (C14H8FNO2) C, H, N, F.

Activation and coupling of the product as above gave bis [(5-fluoroakrydyno-4-carboxamido) propyl] methylamine (11) (96%), mp (HCl salt) 188 ° C (dec), ¹ H NMR (CDCl3) δ 2.06 (quintet, J = 7.2Hz, 4H, 2xCH2CH2CH2), 2.38 (s, 3H, CH3), 2.73 (t, J = 7.6Hz, 4H, 2xCH2NCH3) , 3.72 (q, J = 6.3Hz, 4H, 2xCH2NH), 7.26 (m, 4H, ArH), 7.56 (m, 2H, ArH), 7.59 (dd, J = 8.4, 7.2 Hz, 2H, H-2), 7.99 (dd, J = 8.4, 1.4 Hz, 2H, H-1), 8.64 (d, J = 0.6 Hz, 2 H, H-9), 8.93 (dd, J = 7.1, 1.5 Hz, 2 H, H-3), 11.61 (t, J = 4, 57 Hz, 2H CONH).

Example 13: Preparation of compound 12 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem., 1987, 30, 664) 5-chloroakrydyno-4-carboxylic acid gave bis [(5-chloroakrydyno-4-carboxamido) -propyl] methylamine (12) (62%) as a yellow oil, ¹ H NMR (CDCl3) δ 2.01-2.05 (m, 4H, 2xCH2CH2CH2), 2.33 (s, 3H, NCH3), 2.64 (t, J = 7.5Hz, 4H, 2xCH2NCH3), 3, 72 (q, J = 6.4, Hz, 4H, 2xCH2NH), 7.33 (dd, J = 8.4, 7.3Hz, 2H, H-7), 7.58 (dd, J = 8.2, 7.2 Hz, 2 H, H-2), 7.74-7.77 (m, 4 H, H-6 and H-8), 7.96 (dd, J = 8, 4, 1.5Hz, 2H, H-1), 8.64 (s, 2H, H-9), 8.91 (dd, J = 7.1, 1.5Hz, 2H, H -3), 11.74 (br t, J = 5.3 Hz, 2H, 2xNH).

HRMS (FAB ⁺⁾ m / z calcd for C35H32 Cl2N5O2 ³⁵ 624.1933 (MH ^+), found 624.1940.

Example 14: Preparation of Compound 13 of Table I by the method of Scheme 1. Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-bromo-9-oxoacridane-4-carboxylic acid as above gave 5- bromoakrydyno-4-carboxylic acid (70%), mp (MeOH / H 2 O) 327 ° C (dec), ¹ H NMR [(CD3) 2 SO) δ 7.71 (dd, J = 8.3, 7.4 Hz , 1H, H-2), 7.94 (dd, J = 8.4, 7.1Hz, 1H, H-7), 8.40 (dd, J = 8.7, 0.8Hz , 1H, ArH), 8.50 (dd, J = 7.3, 1.0Hz, 1H, ArH), 8.64 (dd, J = 8.3, 1.3Hz, 1H, ArH), 8.85 (dd, J = 7.1, 1.3 Hz, 1H, ArH), 9.66 (s, 1H, H-9), 16.77 (br s, 1H, COOH). Analysis (C14H8BrNO2) C, H, N, Br.

Activation and coupling of the product as above gave bis [(5-bromoakrydyno-4-carboxamido) propyl) -methyl-amine (13) (800), mp (HCl salt) 212-214 ° C, ¹ H NMR (CDCl3) δ 2 .05 (quintet, J = 7.3Hz, 4H, 2xCH2CH2CH2), 2.33 (s, 3H, CH3), 2.63 (t, J = 7.6Hz, 4H, 2xCH2NCH3), 3 , 73 (q, J = 6.7Hz, 4H, 2xCH2NH), 7.28 (dd, J = 8.2, 7.2Hz, 2H, H-2), 7.57 (dd, J = 8.4, 7.2Hz, 2H, H-7), 7.81 (dd, J = 8.5, 0.9Hz, 2H, H-1), 7.91 (m, 4 H, ArH), 8.64 (s, 2 H, H-9), 8.90 (dd, J = 7.1, 1.5 Hz, 2 H, H-3), 11.72 (t, J = 5.6 Hz, 2H).

Example 15: Preparation of compound 15 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem., 1987, 30, 664] 6-methoxyacridine-4-carboxylic acid gave bis [(6-methoxyacridine-4-carboxamido) -propyl] -methylamine (15) (24%), m.p. (HCl salt) 204- 206 ° C (dec), ¹ H NMR (CD3) 2 SO] δ 2.20 (m, 4 H, 2xCH2CH2CH2), 2.85 (d, J = 4.65 Hz, 3 H, CH3), 3.59 -3.69 (m, 8H, 4xCH2), 3.95 (s, 6H, 2xOCH3), 7.17 (d, J = 8.9Hz, 1H, ArH), 7.57 (br s , 1H, ArH), 7.64 (t, J = 7.7Hz, 1H, H-2), 7.70 (d, J = 0.8Hz, 1H, H-5), 7 , 97 (d, J = 8.35 Hz, 1H, ArH), 8.25 (d, J = 8.35 Hz, 1H), 8.63 (d, J = 6.55 Hz, 1H , ArH), 9.11 (s, 1H, H-9), 10.74 (br s, 1H, NH), 11.21 (br s, 2H, 2xCONH), 14.43 (br s , 1H, NH).

Example 16: Preparation of Compound 16 of Table I by the Process of Scheme 1. Reduction of 6-fluoro-9-oxoacridane-4-carboxylic acid as above gave 6-fluoroacridine-4-carboxylic acid (91%), melting point (MeOH / H2O) 268-270 C, ¹ H NMR [(CD3) 2 SO] δ 7.76 (td, J = 8.9, 2.5 Hz, 1 H, H-7), 7.86 ( td, J = 8.9, 2.5Hz, 1H, H-2), 8.21 (dd, J = 10.6, 2.4Hz, 1H, H-6), 8.45 ( dd, J = 9.3, 6.4 Hz, 1H, H-1), 8.58 (dd, J = 8.4, 1.3 Hz, 1H, ArH), 8.77 (dd, J = 7.1, 1.5 Hz, 1H, ArH), 9.60 (s, 1H, H-9), 16.67 (br s, 1H, COOH).

Activation and coupling of the product as above gave bis [(6-fluoroakrydyno-4karboksyamido) propyl] methylamine (16) (57%), mp (HCl salt) 165.5 ° C (dec), ¹ H NMR (CDCl3) δ 2.04 (quintet, J = 7.1 Hz, 4H, 2xCH2CH2CH2), 2.39 (s, 3H, CH3) 2.72 (t, J = 7.4Hz, 6H, 2xCH2NCH3), 3.45 (q, J = 6.4Hz, 4H, 2xCH2NH), 7.28 (ddd, J = 9.2, 8.0, 2.4Hz, 2H, H-2), 7, 62 (dd, J = 8.35, 7.2 Hz, 2H, H-7), 7.69 (dd, J = 7.6, 2.4 Hz, 2H, H-3), 7, 89 (dd, J = 9,2,6,

Hz, 2H, H-8), 8.05 (dd, J = 8.3, 1.5Hz, 2H, H-1), 8.74 (s, 2H, H-9), 8 . 95 (dd, J = 7.2,1.5Hz, 2H,

H-5), 11.57 (t, J = 4.85 Hz, 2H, 2xCONH). Analysis (0 ₃₅ Η ₃₁ Ρ ₂ Ν ₅ Ο ₂ Η0Η 4Η ₂ Ο) C, H, N,

PL 193 669 B1

Example 17: Preparation of compound 17 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem., 1987, 30, 664] 6-chloroacridine-4-carboxylic acid gave bis [(6-chloroacridine-4-carboxamido) -propyl] methylamine (17) (76%), m.p. (HCl salt) 216-218 ° C, ¹ H NMR [(CD3) 2 SO] δ 2.17 (quintet, J = 6.9 Hz, 4 H, 2xCH2CH2CH2), 2.87 (d, J = 4.7 Hz, 3 H, CH3) , 3.30 (m, 4H, 2xCH2), 3.63 (m, 4H, 2xCH2), 7.47 (dd, J = 8.9, 2.0Hz, 1H, ArH), 7, 69 (t, J = 7.7Hz, 1H, ArH), 8.06 (d, J = 9.0Hz, 1H, H-8), 8.28 (dd, J = 8.3, 1.3 Hz, 1H, ArH), 8.38 (d, J = 1.7Hz, 1H, H-5), 8.64 (dd, J = 7.1, 1.3Hz, 1 H, ArH) 9.16 (s, 1H, H-9), 10.17 (br s, 1H, NH), 11.09 (t, J = 5.7Hz, 2H, 2xNH), 11.44 (br s, 2H, 2xCONH).

Example 18: Preparation of compound 21 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 7-metyloakrydyno-4-carboxylic acid gave bis [(7-metyloakrydyno-4-carboxamido) -propyl] methylamine (21) (73%) as a yellow oil, ¹ H NMR (CDCl3) δ 2 03-2.10 (m, 4H, 2xCH2CH2CH2), 2.34 (s, 6H, 2xCH3), 2.39 (s, 3H, NCH3), 2.80 (t, J = 7.6Hz , 4 H, 2xCH2NCH3), 3.73 (q, J = 6.1 Hz, 4H, 2xCH2NH), 7.30 (br s, 2H, H-8), 7.35 (dd, J = 8 , 8, 1.9Hz, 2H, H-6), 7.55 (dd, J = 8.4, 7.1Hz, 2H, H-2), 7.77 (d, J = 8 , 9 Hz, 2 H, H-5), 7.92 (dd, J = 8.4, 1.5 Hz, 2 H, H-1), 8.36 (s, 2 H, H-9) , 8.84 (dd, J = 7.1, 1.5 Hz, 2H, H-3), 11.74 (br t, J = 5.0 Hz, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C37H39N5O2 584.3026 (MH ⁺ ), found 584.3043.

Example 19: Preparation of compound 23 of Table I by the method of Scheme 1. A similar reaction of 2-iodoisophthalic acid and 4-isopropylaniline gave 2 - [(4-isopropyl) phenylamino] -isophthalic acid (62%), melting point ( EtOAc / petroleum ether) 208 ° C (dec), ¹ H NMR [(CD3) 2 SO] δ 1.16 (d, J = 6.9 Hz, 6 H, 2xCH3), 2.78-2.82 (m , 1H, CH), 6.83 (d, J = 8.4Hz, 2H, H-2 'and H-6' or H-3 'and H-5'); 6.97 (t, J = 7.7 Hz, 1H, H-5), 7.07 (d, J = 8.5 Hz, 2H, H-3 'and H-5' or H-2 'and H-6'), 7.92 (d, J = 7.7Hz, 2H, H-4 and H-6), 9.66 (br s, 1H, NH), 12.89 ( br s, 2H, 2xCOOH). Analysis of (C17H17NO4) C, H, N.

Cyclization of the product as above gave 7-isopropyl-9-oksoakrydano-4-carboxylic acid (95%) mp (H2O / MeOH / TEA / AcOH) 289-291 ° C, ¹ H NMR [(CD3) 2 SO] δ 1 , 28 (d, J = 6.9Hz, 6H, 2xCH3), 3.03-3.07 (m, 1H, CH), 7.34 (t, J = 7.7Hz, 1H, H-2), 7.70 (dd, J = 8.6, 1.6 Hz, 1H, H-6), 7.74 (d, J = 8.5 Hz, 1H, H-5) 8.07 (d, J = 1.6 Hz,

H-8), 8.43 (dd, J = 7.5, 1.6 Hz, 1H, H-3), 8.54 (dd, J = 7.9, 1.6 Hz, 1H, H-1), 11.93 (s, 1H, NH), 13.80 (br s, 1H, COOH). Analysis of (Ο ₁₇ Η ₁₅ ΝΟ ₃ 0.25 H ₂ O) C, H, N.

Reduction of the product as above gave 7-izopropylakrydyno-4-carboxylic acid (51%), mp (acetone) 186-187 ° C, ¹ H NMR [(CD _{3) 2} SO] δ 1.37 (d, J = 6.9 Hz, 6 H, 2 xCH _3), 3.15-3.25 (m, 1H, CH), 7.84 (dd, J = 8.3,

7.2 Hz, 1H, H-2), 8.03 (dd, J = 9.0, 1.8 Hz, 1H, H-6), 8.11 (br s, 1H, H- 8), 8.27 (d, J = 9.0 Hz, 1H, H-5), 8.54 (dd, J = 8.5, 1.0 Hz, 1H, H-1), 8 , 73 (dd, J = 7.0, 1.2 Hz, 1H, H-3), 9.45 (s, 1H, H-9), 17.10 (br s,

H COOH). Analysis (C17H15NO2) C, H, N.

Activation and coupling of the product as above gave bis [(7-izopropylakrydyno-4karboksyamido) -propyl] methylamine (23) (73%) as a yellow oil, ¹ H NMR (CDCl3) δ 1.33 (d, J = 6.9 Hz, 12H, 4xCH3), 2.04-2.08 (m, 4H, 2xCH2CH2CH2), 2.38 (s, 3H, NCH3), 2.74 (t, J = 7.4Hz, 4 H, 2xCH2NCH3), 3.03-3.06 (m, 2H, 2xCH), 3.74 (q, J = 6.2Hz, 4H, 2xCH2NH), 7.58 (dd, J = 8, 3.7.2Hz, 2H, H-2), 7.60-7.66 (m, 4H, H-6 and H-8), 8.01 (d, J = 9.5Hz,

H, H-5), 8.03 (dd, J = 8.3, 1.5 Hz, 2 H, H-1), 8.66 (s, 2 H, H-9), 8.88 ( dd, J = 7.2, 1.5 Hz, 2H, H-3), 11.85 (br t, J = 5.1 Hz, 2H, 2xNH).

HRMS (FAB ⁺ ) m / z calcd for C41H46N5O2 640.3652 (MH ⁺ ), found 640.3657.

Example 20: Preparation of compound 24 of Table I by the method of Scheme 1. A similar reaction of 2-iodoisophthalic acid and 4-t-butylaniline gave 2 - [(4-t-butyl) phenylamino] -isophthalic acid (93%). mp (EtOAc / petroleum ether) 221-222 ° C, ¹ H NMR [(CD3) 2 SO] δ 1.24 (s, 9 H, 3xCH3), 6.84 (d, J = 8.7 Hz, 2 H, H-2 'and H-6' or H-3 'and H-5'), 6.99 (t, J = 7.7 Hz, 1H, H-5), 7.21 (d, J = 8.6 Hz, 2 H, H-3 'and H-5' or H-2 'and H-6'), 7.93 (d, J = 7.8 Hz, 2 H, H-4 and H-6), 9.65 (br s, 1H, NH) and 12.99 (br s, 2H, 2xCOOH) Analysis (C18H13NO2) C, H, N.

Cyclization of the product as above gave 7-tert-butyl-9-oksoakrydano-4-carboxylic acid (79%), mp (H2O / MeOH) 326-327,5 ° C, ¹ H NMR [(CD3) 2 SO] δ 1.37 (s, 9H, 3xCH3), 7.34 (t, J = 7.8Hz, 1H, H-2), 7.74 (d, J = 8.8Hz, 1H, H -5), 7.88 (dd, J = 8.8, 2.3Hz, 1H, H-6), 8.19 (d, J = 2.4Hz, 1H, H-8), 8.43 (dd, J = 7.6, 1.6 Hz, 1H,

PL 193 669 B1

H-3), 8.53 (dd, J = 8.0, 1.6 Hz, 1H, H-1), 11.96 (s, 1H, NH), and 13.85 (br s, 1 H, COOH)). Analysis (C18H17NO3) C, H, N.

Reduction of the product as above gave 7-tert-butylakrydyno-4-carboxylic acid (62%), mp (acetone) 253-253,5 ° C, ¹ H NMR [(CD3) 2 SO] δ 1.46 (s, 9 H, 3xCH3), 7.83 (dd, J = 8.4, 7.1 Hz, 1H, H-2), 8.18 (d, J = 1.7 Hz, 1H, H-8 ), 8.22 (dd, J = 9.2, 2.0 Hz, 1H, H-6), 8.27 (d, J = 9.2 Hz, 1H, H-5), 8, 52 (dd, J = 8.4, 1.2 Hz, 1H, H-1), 8.72 (dd, J = 7.1, 1.2 Hz, 1H, H-3), 9, 46 (s, 1H, H-9), 17.11 (br s, 1H, COOH)). Analysis (C18H17NO2) C, H, N.

Activation and coupling of the product as above gave bis [(7-t-butylakrydyno-4-carboxamido) propyl] methylamine (24) (82%) as a yellow oil, ¹ H NMR (CDCl3) δ 1.43 (s, 18 H, , 6xCH3), 2.04-2.07 (m, 4H, 2xCH2CH2CH2), 2.38 (s, 3H, NCH3), 2.72 (t, J = 7.4Hz, 4H, 2xCH2NCH3) , 3.74 (q, J = 6.8, 5.6 Hz, 4H, 2xCH2NH), 7.59 (dd, J = 8.3, 7.2Hz, 2H, H-2), 7 . 81 (d, J = 2.1 Hz, 2H, H-8), 7.88 (dd, J = 9.2, 2.1 Hz, 2H, H-6), 8.05 (dd , J = 8.3, 1.4 Hz, 2 H, H-1), 8.07 (d, J = 9.3 Hz, 2 H, H-5), 8.73 (s, 2 H, H-9), 8.89 (dd, J = 7.2, 1.5 Hz, 2 H, H-3) and 11.87 (br t, J = 5.1 Hz, 2 H, 2x (CONH )).

HRMS (FAB ⁺ ) m / z calcd for C43H50N5O2 668.3965 (MH ⁺ ), found 668.3963.

Example 21: Preparation of compound 25 of Table I by the method of Scheme 1. Reduction of the known [Denny et al., J. Med. Chem., 1987, 30, 658] 7-phenyl-9-oksoakrydano-4-carboxylic acid as above gave 7-fenyloakrydyno-4-carboxylic acid (69%), mp (acetone) 239-241 ° C, ¹ H, NMR [(CD3) 2SO] δ 7.49 (t, J = 7.3 Hz, 1H, H-4 '), 7.60 (t, J = 7.3 Hz, 2H, H-3' and H-5 '), 7.86 (dd, J = 8.4, 7.1 Hz, 1H, H-2), 7.96 (d, J = 7.3Hz, 2H, H- 2 'and H-6'), 8.43 (br s, 2H, H-6 and H-8), 8.58 (dd, J = 8.5, 1.2 Hz, 1H, H- 1), 8.64 (br s, 1H, H-5), 8.74 (br d, J = 7.1Hz, 1H, H-3), 9.56 (s, 1H, H -9), 16.93 (br s, 1H, COOH). Analysis (C20H13NO2) C, H, N

Activation and coupling of the product as above gave bis [(7-fenyloakrydyno-4-carboxamido) -propyl] methylamine (25) (90%), mp (CH2Cl2 / MeOH) 162-163 ° C, ¹ H NMR (CDCl3) δ 2.07-2.14 (m, 4H, 2xCH2CH2CH2), 2.42 (s, 3H, NCH3), 2.82 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3, 77 (q, J = 6.5, 5.6 Hz, 4H, 2xCH2NH), 7.40-7.52 (m, 4H, H-2 and H-4 'or H-3' and H- 5 '), 7.48-7.52 (m, 4H, H-3' and H-5 'or H-2 and H-4'), 7.63-7.65 (m, 4H, H-2 'and H-6'), 7.82-7.84 (m, 4H, H-6 and H8), 7.87 (dd, J = 8.4, 1.4Hz, 2H , H-1), 7.97 (d, J = 9.5 Hz, 2 H, H-5), 8.54 (s, 2H, H-9), 8.80 (dd, J = 7 , 1.1.5 Hz, 2H, H-3), 11.69 (br t, J = 5.2Hz, 2H, 2NH).

HRMS (FAB ⁺ ) m / z calcd for C47H42N5O2 708.3339 (MH ⁺ ), found 708, 3351.

Example 22: Preparation of compound 26 of Table I by the method of Scheme 1. Activation and coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 7-methoxyacridine-4-carboxylic acid gave bis [(7-methoxyacridine-4-carboxamido) propyl] methylamine (26) (93%) as yellow oil.

¹ H NMR (CDCl3) δ 2.02-2.06 (m, 4 H, 2xCH2CH2CH2), 2.37 (s, 3 H, NCH 3), 2.74 (t, J = 7.4 Hz, 4 H , 2xCH2NCH3), 3.72 (q, J = 6.7, 5.6 Hz, 4H, 2xCH2NH), 3.88 (s, 6H, OCH3), 6.89 (d, J = 2.7 Hz, 2H, H-8), 7.32 (dd, J = 9.3, 2.7Hz, 2H, H-6), 7.54 (dd, J = 8.2, 7.2 Hz, 2H, H-2), 7.85 (d, J = 9.3Hz, 2H, H-5), 7.94 (dd, J = 8.4, 1.5Hz, 2H , H-1), 8.44 (s, 2H, H-9), 8.82 (dd, J = 7.1, 1.5Hz, 2H, H-3), 11.69 (br t, J = 5.1 Hz, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O4 616.2924 (MH ⁺ ), found 616.2927.

Example 23: Preparation of compound 27 of Table I by the method of Scheme 1. Known reduction [Atwell et al., J. Med. Chem., 1987, 30, 658] 7-fluoro-9-oxoacridane-4-carboxylic acid as above gave 7-fluoroacridine-4-carboxylic acid (95%), mp (MeOH / H2O) 267-268 ° C, ¹ H NMR [(CD3) 2 SO] δ 7.87 (dd, J = 8.4, 7.0 Hz, 1 H, H-2), 8.01 (ddd, J = 9.5, 8.5 , 2.3Hz, 1H, H-6), 8.13 (dd, J = 9.3, 2.8Hz, 1H, H-8), 8.45 (dd, J = 9.6 , 5.3Hz, 1H, H-5), 8.54 (dd, J = 8.5, 1.3Hz, 1H, H-1), 8.73 (dd, J = 6.9 , 1.4Hz, 1H, H-3), 9.47 (s, 1H, H-9), 16.53 (br s, 1H, COOH). Analysis (C14H8FNO2) C, H, N, F.

Activation and coupling of the product as above gave bis [(7-fluoroakrydyno-4-carboxamido) propyl] methylamine (27) (57%), mp (HCl salt) 173.5 ° C (dec), ¹ H NMR ( CDCl3) δ 2.04 (quintet, J = 7.07Hz, 4H, 2xCH2CH2CH2), 2.73 (t, J = 7.4 HZ, 4H, 2xCH2NCH3), 3.73 (q, J = 6 , 3 Hz, 4 H, 2xCH2NH), 7.32 (dd, J = 8.6, 2.7 Hz, 2H, H-3), 7.42 (ddd, J = 9.4, 8.1 , 2.7Hz, 4H, H-6), 7.63 (dd, J = 7.7, 7.2Hz, 2H, H-2), 7.96 (dd, J = 9.1 , 4.9 Hz, 2H, H-5),

PL 193 669 B1

7.99 (dd, J = 7.7, 1.5Hz, 2H, H-1), 8.56 (s, 2H, H-9), 8.89 (dd, J = 7.0 , 1.5Hz, 2H, H-3), 11.50 (t,

J = 4.95 Hz, 2H, 2xCONH).

Example 24: Preparation of compound 28 of Table I by the method of Scheme 1. Activation of coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] 7-chloroakrydyno-4-carboxylic acid gave bis [(7-chloroakrydyno-4-carboxamido) -propyl] methylamine (28) (75%) as a yellow oil, ¹ H NMR (CDCl3) δ 2 03-2.07 (m, 4H, 2xCH2CH2CH2), 2.38 (s, 3H, NCH3), 2.75 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.73 (q , J = 6.1Hz, 4H, 2xCH2NH), 7.45 (dd, J = 9.2, 2.3Hz, 2H, H-6), 7.63-7.67 (m, 4 H, H-2 and H-8), 7.84 (d, J = 9.2 Hz, 2 H, H-5), 7.99 (dd, J = 8.4, 1.5 Hz, 2 H, H-1), 8.48 (s, 2 H, H-9), 8.93 (dd, J = 7.2, 1.5 Hz, 2 H, H-3), 11.42 ( br t, J = 5.0 Hz, 2xCONH).

HRMS (FAB ⁺⁾ m / z calcd for (MH ^{+) 35} C35H32 Cl2N5O2 624.1933, Found 624.1923.

Example 25: Preparation of compound 29 of Table I by the method of Scheme 1. Reduction of 7-bromo-9-oxoacridane-4-carboxylic acid as above gave 7-bromoacridine-4-carboxylic acid (59%), melting point (MeOH) / H 2 O) 304 ° C (dec), ¹ H NMR [(CD3) 2 SO] δ 7.87 (dd, J = 8.4, 7.2 Hz, 1 H, H-2), 8.13 (dd , J = 9.2,2.2 Hz, 1H, H-6),

8.32 (d, J = 9.2 Hz, 1H, H-5), 8.56 (dd, J = 8.5, 1.3 Hz, 1H, H-1), 8.66 (d, J = 2.1Hz, 1H, H-8), 8.74 (dd, J = 7.1, 1.4Hz, 1H, H-3), 9.48 (s, 1H, H -9), 16.49 (s, 1H, COOH). Analysis (C14H8BrNO2) C, H, N, Br.

Activation and coupling of the product as above gave bis [(7-bromoakrydyno-4-carboxamido) propyl] methylamine (29) (25%), mp (HCl salt) 138-142 ° C, ¹ H NMR (CDCl3) δ 2.04 (quintet, J = 7.0Hz, 4H, 2xCH2CH2CH2), 2.38 (s, 3H, CH3), 2.75 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.73 (q, J = 6.3Hz, 4H, 2xCH2NH), 7.55 (dd, J = 9.1, 2.1Hz, 2H, H-6), 7.66 (dd, J = 8.3, 7.2 Hz, 2 H, H -2), 7.76 (d, J = 9.2 Hz, 2 H, H-5), 7.83 (d, J = 2, 1 Hz, 2 H, H-8), 7.99 (dd, J = 8.2, 1.4 Hz, 2 H, H-1), 8.46 (s, 2 H, H-9), 8.94 (dd, 7.0, 1.5Hz, 2H, H-3), 11.41 (t, J = 4.9Hz,

H, 2x CONH).

Example 26: Preparation of compound 30 of Table I by the method of Scheme 1. Activation of coupling of the known [Atwell et al., J. Med. Chem. 1987, 30, 664] of 8-methyl-9-oksoakrydano-4-carboxylic acid as above gave bis [(8-metyloakrydyno-4-carboxamido) propyl] methylamine (30) as a yellow oil (61%), ¹ H NMR (CDCl3) δ 2.03-2.10 (m, 4H, 2xCH2CH2CH2), 2.39 (s, 3H, NCH3), 2.66 (s, 6H, 2xCH3), 2.79 (t, J = 7 , 5Hz, 4H, 2xCH2NCH3), 3.74 (q, J = 6.2Hz, 4H, 2xCH2NH), 7.09 (d, J = 6.9Hz, 2H,

H-5 or H-7), 7.49 (dd, J = 8.8, 6.8 Hz, 2 H, H-6), 7.62 (dd, J = 8.4, 7.1 Hz , 2 H, H -2), 7.83 (d, J = 8.7

Hz, 2H, H-7 or H-5), 8.04 (dd, J = 8.3, 1.5 Hz, 2H, H-1), 8.74 (s, 2H, H- 9), 8.91 (dd, J = 7.1, 1.5 Hz,

H, H-3) and 11.78 (br t, J = 4.8 Hz, 2xCONH);

HRMS (FAB ⁺ ) m / z calcd for C37H38N5O2 584.3026 (MH ⁺ ), found 584.3033. Analysis (C ₃₇ H ₃₇ N ₅ O ₂ O, 5H ₂ O) c, h, n.

Example 27: Preparation of compound 31 of Table I by the method of Scheme 1. Activation and coupling of the known chloroacridine-4-carboxylic acid gave bis [(8-chloroacridine-4-carboxamido) propyl] methylamine (31) as a yellow oil (88 %), ¹ H NMR (CDCl3) δ 2.04-2.10 (m, 4 H, 2xCH2CH2CH2), 2.40 (s, 3 H, NCH3), 2.84 (t, J = 7.4 Hz , 4 H, 2xCH2NCH3), 3.74 (q, J = 6.1, Hz, 4H, 2CH2NH), 7.10 (dd, J = 7.3, 0.8Hz, 2H, H-5 or H-7),

7.33 (dd, J = 8.8, 7.3 Hz, 2H, H-2 or H-6), 7.65 (dd, J = 8.3, 7.2 Hz, 2H, H-6 or H-2), 7.73 (d, J = 8.7

Hz, 2H, H-7 or H-5), 8.06 (dd, J = 8.8, 1.5 Hz, 2H, H-1), 8.86 (s, 2H, H-9) . 8.90 (dd, J = 7.2,1.5Hz,

2H, H-3) and 11.36 (br t, J = 5.0 Hz, 2H, 2xCONH);

HRMS (FAB ⁺⁾ m / z calcd for C35H32 Cl2N5O2 ³⁵ 624.1933 (MH ^+), found 624.1939. Analysis (C35H31Cl2N5O2) C, H, N.

Example 28: Preparation of compound 37 of Table I by the method of Scheme 1. Activation and coupling of acridine-2-carboxylic acid gave bis [(acridine-2-carboxamido) propyl] -methylamine (37) (60%), m.p. (CH2Cl2 / petroleum ether) 199-200 ° C, ¹ H NMR (CDCl3) δ 1,85-1,91 (m, 4 H, 2xCH2CH2CH2), 2.36 (s, 3 H, NCH 3), 2.59 (t, J = 6.2Hz, 4H, 2xCH2NCH3), 3.65 (dd, J = 6.3, 5.9Hz, 4H, 2xCH2NH), 7.41 (ddd, J = 8.4 , 6.6, 1.0 Hz, 2H, H-6 or H-7), 7.64 (br t, J = 5.3 Hz, 2H, 2xNH), 7.70 (ddd, J = 8.9, 6.6, 1.4 Hz, 2H, H-7 or H-6), 7.75 (d, J = 8.1 Hz, 2H, H-5 or H-8), 8 .06 (dd, J = 9.1, 1.9 Hz, 2H, H-3), 8.13 (dd, J = 8.9, 0.8 Hz, 2H, H-8 or H- 5), 8.20 (d, J = 9.1 Hz, 2H, H-4), 8.36 (d, J = 1.9 Hz, 2H, H-1) and 8.52 (s , 2H, H-9).

HRMS (FAB ⁺ ) m / z calcd for C35H34N5O2 556.2713 (MH ⁺ ), found 556.2694. Analysis (C35H33N5O2) C, H, N.

PL 193 669 B1

Example 29: Preparation of compound 33 of Table I by the method of Scheme 2. A solution of methyl 2- [N- (2-carboxyphenyl) amino] benzoate [Rewcastle and Denny, Synth. Comm., 1987, 17, 309] (10 g, 36.9 mmol) in dry THF (200 ml) was treated with CDI (8.97 g, 55.4 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour then added slowly to a suspension of NaBH4 (7.00 g) in H 2 O (200 ml) without isolating the intermediate imidazolide. When the reaction was judged complete (tlc; approximately 30 minutes), the mixture was quenched with concentrated HCl and partitioned between CH2Cl2 (200 mL) and NaHCO3 (200 mL) and the organic layer was dried with Na2SO4. Removal of the solvent and filtration of the residue through a plug of flash-grade silica gel in petroleum ether / EtOAc (4: 1) gave methyl 2- [N- (2-hydroxymethyl) phenylamino] benzoate, (7.85 g, 830), m.p. (CH2Cl2 / petroleum ether) to 69,0-71,0 ° C, ¹ H NMR (CDCl3) δ 1.93 (br s, 1H, OH), 3.91 (s, 3 H, COOCH 3), 4, 72 (s, 2H, CH2OH), 6.74 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H, H-5), 7.08-7.44 (m, 6 H, H-3, 3 ', 4, 4', 5 ', 6'), 7.97 (dd, J = 8.0, 1.6 Hz, 1H, H-6), 9.59 ( br s, 1H, NH). Analysis (C15H14NO3) C, H, N.

A stirred solution of the above alcohol (7.74 g, 30 mmol) in acetone (200 mL) was treated with a MnO2 suspension (10 g) at room temperature for 3 days until all starting material (tlc) was consumed. MnO2 was filtered off (Celite) and acetone was removed under reduced pressure to give methyl 2- [N- (2-formyl) phenylamino] benzoate as a light yellow solid (7.70 g, 100%). A sample crystallized from (EtOAc / petroleum ether had a melting point 110,0-112,0 ° C, ¹ H NMR (CDCl3) δ 3.95 (s, 3 H, COOCH3), 6,95-7,03 (m, 2 H, H-4 ', 5), 7.41-7.45 (m, 2H, H-5', 6), 7.50 (br d, J = 8.5Hz, 1H, H -3 or H-6 '), 7.61 (br d, J = 8.2 Hz, 1H, H-6' or H-3), 7.65 (dd, J = 7.7, 1, 7 Hz, 1H, H-3 '), 8.01 (dd, J = 7.9, 1.7Hz, 1H, H-6), 10.00 (s, 1H, CHO), 11 . 26 (br s, 1H, NH).

Analysis (C15H13NO3) C, H, N.

The above aldehyde (210 mg, 0.8 mmol) was placed in a two-necked flask which was then purged with N2, added trifluoroacetic acid (10 mL) and the solution stirred for 15 hours at room temperature under N2. The trifluoroacetic acid was then removed under reduced pressure, and the flask containing the resulting crude methyl acridine-4-carboxylate was purged with ^# nitrogen. A degassed 2 M NaOH solution in aq. EtOH (1: 1) (35 ml) was then added and the mixture was stirred for 3 hours at 50 ° C under N2 until a clear solution was obtained, then neutralized with glacial AcOH and extracted with EtOAc (3 x 50 ml ). Evaporation of the organic layer and silica gel chromatography of the residue, eluting with EtOAc / petroleum ether (1: 4) gave acridine-4-carboxylic acid (160mg, 870) mp (Me2CO) 196-197 ° C [Atwell et al., J. Med. Chem. 1987, 30, 664, mp 202-204 ° C].

^# Diluting the residue at this point with CH2Cl2 and carefully neutralizing the Et3N solution, then removing the solvent under reduced pressure and filtering the residue through a short column of silica gel in EtOAc / petroleum ether (1: 3) gave pure methyl acridine-4-carboxylate as an orange oil, ¹ H NMR (CDCl3) δ 4.12 (s, 3H, COOCH3), 7.53-7.58 (m, 2H, H-2 and H-6 or H-7), 7.79 (ddd, J = 8.8, 6.6, 1.4 Hz, 1H, H-7 or H-6), 8.00 (dd, J = 8.0, 1.0 Hz, 1H, H-1 ), 8.12-8.14 (m, 2H, H-5.8), 8.30 (dd, J = 8.7, 0.9Hz, 1H, H-3), 8.80 (s, 1H, H-9).

A suspension of acridine-4-carboxylic acid (4.00 g, 17.9 mmol) in DMF (25 mL) was treated with CDI (3.49 g, 21.5 mmol) and stirred at 30 ° C for 2 hours. After cooling, the mixture was diluted with CH2Cl2 (25 mL) then with petroleum ether (75 mL) to complete the precipitation of the product that was collected, washed with petroleum ether / CH2Cl2 (4: 1) and dried to give the moisture-sensitive imidazolide (3.81 g, 78%). It was reacted with N, N-bis (3-aminopropyl) methylamine according to the procedure described above. The product was purified by chromatography on alumina-90, eluting with CH2Cl2 / MeOH (20: 1) to give bis [(acridine-4-carboxamido) propyl] -methylamine (33) (83%) as a foam, ¹ H NMR [( CD3) 2SO] δ 9.06 (s, 2H, H-9), 8.65 (d, J = 7.1 Hz, 2H, H-3), 8.24 (d, J = 8, 5 Hz, 2 H, ArH), 8.00 (t, J = 9.5 Hz, 4 H, ArH), 7.8-7.6 (m, 4 H, ArH), 7.45 (t, J = 7.5 Hz, 2H, ArH), 3.58 (q, J =

6.2Hz, 4H, 2xNHCH2), 2.65 (t, J = 7.0Hz, 4H, 2xCH2NCH3), 2.29 (s, 3H, CH3), 1.91 (quintet, J = 6.9Hz, 4H, 2xCH2CH2CH2). Crystallization from MeOH / EtOAc / HCl gave the trihydrochloride salt, mp 168-170 ° C.

Analysis of (Ο ₃₅ Η ₃₃ Ν ₅ Ο ₂ · 3ΗΟ1) Ο, Η, Ν, Cl.

Example 30: Preparation of compound 34 of Table I by the method of Scheme 2. Reaction of acridine-4-carboxylic acid imidazolide with N, N-bis (2-aminoethyl) amine as above, then

GB 193 669 B1 crystallization of the crude product from MeOH / H ₂ O, gave bis [2- (acridine-4-carboxamido) ethyl] amine (34) (84%), ¹ H NMR [(0D3) 2 SO] δ 11.57 (t, J = 5.0Hz, 2H, 2xOONH), 8.80 (s, 2H, H-9), 8.46 (d, J = 7.1Hz, 2H, H-3) , 8.08 (d, J = 8.4 Hz, 2-H, ArH), 7.92 (d, J = 8.7 Hz, 2H, ArH), 7.79 (d, J = 8, 1Hz, 2H, ArH), 7.55 (t, J = 7.7Hz, 2H, ArH), 7.41 (t, J = 7.6Hz, 2H, ArH), 7.27 (t, J = 7.4Hz, 2H, ArH), 3.73 (q, J = 5.5Hz, 4H, 2xNHOH2), 3.11 (t, J = 5.6Hz, 4H , OH2NH0H2). The trihydrochloride crystallized from MeOH / EtOAc / HOl, mp 182-184 ° 0. Analysis (C ₃₂ H ₂₇ N ₅ O / 3 HCl) 0, H, N, Cl.

Example 31: Preparation of compound 35 of Table I by the method of Scheme 2. Similar reaction of acridine-4-carboxylic acid imidazolide with N, N-bis (3-aminopropyl) amine as above, followed by purification of the product by chromatography on alumina-90 , eluting with CH2Cl2 / MeOH (20: 1), gave bis [3- (acridine-4-carboxamido) propyl] amine (35) (80%) as an oil, ¹ H NMR [(CD3) 2 SO] δ 11.40 (t, J = 5.4Hz, 2H, 2xCONH), 9.19 (s, 2H, H-9), 8.71 (d, J = 7.1Hz, 2H, H-3) , 8.32 (d, J = 8.5Hz, 2H, ArH), 8.18-8.00 (m, 4H, ArH), 7.83-7.62 (m, 4H, ArH ), 7.51 (t, J = 7.5 Hz, 2H, ArH), 3.64 (q, J = 6.0 Hz, 4H, 2xCONHCH2) 2.86 (t, J = 6.7 Hz, 4H, CH2NHCH2) 1.92 (quintet, J = 6.5 Hz, 4H, 2xCH2CH2CH2). Crystallization from MeOH / EtOAc / HCl gave the trihydrochloride salt, mp 171-173 ° C. Analysis (C ₃₄ H ₃₁ N ₅ O ₂ 2 HCl 2 H ₂ O) C, H, N, Cl.

Example 32: Preparation of compound 36 of Table I by the method of Scheme 2. Similar reaction of acridine-4-carboxylic acid imidazolide with 1,4-bis (3-aminopropyl) piperazine as above, and the crude product crystallization from CH2Cl2 / EtOAc / iPr2O, gave N ¹ , N4-bis [(acridine-4-carboxamido) propyl] piperazine (36) (91%), ¹ HNMR [(CD3) 2SO] δ 11.39 (t, J = 5.2 Hz , 2H, 2xCONH), 9.33 (s, 2H, H-9), 8.73 (d, J = 7.0 Hz, 2H, H-3), 8.38 (d, J = 8.5Hz, 2H, ArH), 8.32-8.20 (m, 4H, ArH), 7.97 (t, J = 7.8Hz, 2H, ArH), 7.827.63 ( m, 4H, ArH), 3.57 (q, J = 6.0Hz, 4H, 2xNHCH2), 2.6-2.3 (m, 12H, H-piperazine, 2xCH2CH2CH2N), 1.85 (quintet, J = 6.7 Hz, 4H, CH2CH2CH2). Crystallization from MeOH / EtOAc / HCl gave the tetrachloride salt, mp 248-253 ° C. Analysis (C ₃₈ H ₃₈ N ₆ O / 4HCl) C, H, N, Cl.

Example 33: Preparation of compound 18 of Table I by the method of Scheme 2. Reaction of methyl 2-iodobenzoate and 4-bromoanthranilic acid as described [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 4-bromo-2 - [(2-methoxycarbonylphenyl) amino] benzoic acid (70%), mp (MeOH / H2O) 218-219,5 ° C, ¹ H NMR [( CD3) 2SO] δ 3.85 (s, 3H, COOCH3), 7.08-7.12 (m, 2H, 2xArH), 7.50 (d, J = 1.9Hz, 1H, H -3), 7.57 (d, J = 3.8Hz, 3H, 2xArH), 7.84 (d, J = 8.4Hz, 1H, ArH), 7.93 (d, J = 7.7Hz, 1H, ArH), 10.80 (s, 1H, NH), 13.33 (br s, 1H, COOH). Analysis of (C15H12BrNO4) C, H, N.

The formation of the imidazolide and reduction of the product as above gave crude methyl-2- [N- (5-bromo2'-hydroxymethyl) phenylamino] benzoate (81%), ¹ H NMR [(CD3) 2 SO] δ 3.91 (s, 3H, COOCH3), 4.68 (d, J = 4.8Hz, 2H, CH2), 6.79-6.84 (m, 1H, ArH), 7.17-7.21 (m , 2H, 2xArH), 7.25 (d, J = 8.5Hz, 1H, ArH), 7.40-7.43 (m, 2H, ArH), 7.55 (d, J = 1.8 Hz, 1H, H-6 '). 9.66 (s, 1H, NH). Oxidation of the product as above gave 2- [N- (5'-bromo-2'-formyl) phenylamino] -benzoate (67% over two steps), mp (MeOH / H2 O) 122-123 ° C, ¹ H, NMR [(CD3) 2SO] δ 3.95 (s, 3H, CO2CH3), 7.05-7.11 (m, 2H, ArH), 7.41-7.52 (m, 2H, 2xArH ), 7.58-7.62 (m, 2H, 2xArH), 8.03 (dd, J = 7.9, 1.6Hz, 1H, ArH), 9.93 (s, 1H, CH), 11.33 (br s, 1H, NH). Analysis of (C15H12BrNO3) C, H, N.

Product cyclization as above gave crude methyl 6-bromoacridine-4-carboxylate which was immediately hydrolyzed as above to give 6-bromoacridine-4-carboxylic acid (100% over two steps), mp (MeOH / H2O) 283-285 ° C ¹ H NMR [(CD3) 2 SO] δ 7.87 (dd, J = 8.3, 7.15 Hz, 1 H, H-2), 7.99 (dd, J = 9.0, 1, 9 Hz, 1H, H-7), 8.23 (d, J = 9.1 Hz, 1H, H-8), 8.56 (dd, J = 8.4, 1.4 Hz, 1 H, H-1), 8.70 (s, 1H, H-5), 8.73 (dd, J = 7.06,

1.4 Hz, H-4), 9.57 (s, 1H, H-9), 16.44 (br s, 1H, COOH). Analysis of (C14H8BrNO2) C, H, N.

Activation and coupling of the product as above gave bis [(6-bromoakrydyno-4-carboxamido) propyl] methylamine (18) (91%), mp (HCl salt) 218-221 ° C, ¹ H NMR (CDCl3) δ 2.07 (quintet, J = 7.0Hz, 4H, 2xCH2CH2CH2), 2.41 (s, 3H, CH3), 2.76 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.75 (q, J = 6.4Hz, 4H, 2xCH2NH), 7.42 (dd, J = 8.95, 1.8Hz, 2H, ArH), 7.65 (m, 4H , ArH), 8.03 (dd, J = 8.4, 1.5 Hz, 2 H, ArH), 8.25 (d, J = 0.9 Hz, H-5), 8.67 (s , 2 H, H-9), 8.95 (dd, J = 7.15, 1.5 Hz, 2 H, ArH), 11.45 (t, J = 5.0 Hz, 2 H, CONH) .

Example 34: Preparation of compound 14 of Table I by the method of Scheme 2. A similar reaction of 2-amino-3-trifluoromethylbenzoic acid and methyl 2-iodobenzoate is described in

Bem [Rewcastle and Denny, Synth. Comm. 1987, 17, 309] gave 3-trifluoromethyl-2 - [(2-methoxycarbonyl) phenyl) amino] benzoic acid (51%), mp (MeOH / H2 O) 113-115 ° C, ¹ H NMR [(CD3 ) 2SO] δ 3.89 (s, 3H, CO2CH3), 6.35 (d, J = 8.5Hz, 1H, ArH), 6.78 (t, J = 7.5Hz, 1H , ArH), 7.30 (ddd, J = 7.8, 7.8, 1.6 Hz, 1H, ArH), 7.59 (t, J = 7.8Hz, 1H, ArH), 7.88 (dd, J = 8.0,

1.5Hz, 1H, ArH), 8.03 (d, J = 7.4Hz, 1H, ArH), 8.07 (d, J = 8.07Hz, 1H, ArH), 9 , 49 (s, 1H, NH). 13.15 (br s, 1H, COOH). Analysis (C16H12F3NO2) C, H, N, F.

Create an appropriate imidazolide and immediate reduction of the product as above gave crude 2- [N- (2-hydroxymethyl-6-trifluoromethyl) phenylamino] benzoate (100%) as an oil, ¹ H NMR [(CD3) 2 SO] δ 3.94 (s, 3H, CO2CH3), 4.50 (d, J = 14.0Hz, 1H, CH), 4.72 (d, J = 14.0Hz, 1H, CH), 6.18 (dd, J = 8.6, 0.7Hz, 1H, ArH), 6.72 (ddd, J = 7.7, 7.5, 1.0Hz, 1H, ArH), 7.23 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H, ArH), 7.46 (t, J = 7.8Hz, 1H, ArH), 7.70 (d, J = 7.1 Hz, 1H, ArH), 7.83 (d, J =

7.7 Hz, 1H, ArH), 7.98 (dd, J = 8.0, 1.6Hz, 1H, ArH), 9.25 (s, 1H, NH).

A solution of the above crude ester was oxidised as above to give 2- [N- (6-trifluoromethyl-2-formyl) phenylamino) benzoate (100%), mp (MeOH / H2 O) 122-123 ° C, ¹ H NMR (CDCl3 ) δ 3.96 (s, 3H, CO2CH3), 6.49 (dd, J = 8.3, 0.8Hz, 1H, ArH), 6.79 (td, J = 7.5, 1 .0 Hz, 1H, ArH), 7.25 (ddd, J = 8.3, 6.5, 1.6 Hz, 1H, ArH), 7.50 (t, J = 7.8 Hz, 1H, ArH), 7.9-8.01 (m, 2H, 2xArH), 8.14 (dd, J = 7.8, 1.4Hz, 1H, ArH), 9.71 (br s, 1H, CHO), 10.09 (s, 1H, NH). Analysis (C16H12F3NO2) C, H, N.

Cyclization of this compound followed by hydrolysis as above gave 5-trifluoromethylacridine-4-carboxylic acid (76%), mp (MeOH / H20) 287-288.5 ° C.

¹ H NMR δ 7.89-7.98 (m, 2 H, 2xArH), 8.55 (d, J = 7.0 Hz, 1H, ArH), 8.65 (td, J = 8.7 , 1.3 Hz, 2H, 2xArH), 8.86 (dd, J = 6.9, 1.4Hz, 1H, ArH), 9.74 (s, 1H, H-9), 16 , 13 (br s, 1H, COOH). Analysis (C18H8F3NO4) C, H, N.

Activation and coupling of the product as above gave bis [(5-trifluorometyloakrydyno-4karboksyamido) propyl] methylamine (14) (52%), mp (EtOAc / MeOH) 231-233 ° C, ¹ H NMR [(CD3) 2SO ] δ 1.81 (quintet, J = 7.1Hz, 4H, CH2CH2CH2), 2.42 (s, 3H, NCH3), 2.44 (t, J = 7.1Hz, 4H, CH2NH3 ), 3.51 (q, J = 6.8Hz, 4H, NHCH2CH2), 7.73 (q, J = 7.4Hz, 4H, 4xArH),

8.24-8.29 (m, 4H, 4xArH), 8.42 (d, J = 0.1Hz, 2H, ArH), 8.78 (dd, J = 7.1, 1.5 Hz, 2H, ArH), 9.30 (s, 2H, H-9), 10.97 (t, J = 5.8Hz, 2H, CONH). Analysis (O ₃₇ H ₃₁ F ₆ N ₅ O ₂ ^ 3HOI ^ 2H ₂ O) C, H, N).

Example 35: Preparation of compound 19 of Table I by the method of Scheme 2. Reaction of 4-trifluoromethylanthranilic acid and methyl 2-iodobenzoate by the method described [Rewcastle and Denny, Synth. 0omm. 1987, 17, 309 gave 4-trifluoromethyl-2- (2-methoxycarbonylphenylamino) benzoic acid (43%), mp (MeOH / H ₂ O) 206-207 ° C, ¹ H NMR [(OD ₃ ) ₂ SO] δ 3.87 (s, 3H, OH _{2 OH 3} ), 7.12 (ddd, J = 8.0, 6.1.2.1 Hz, 1H, H-5 '), 7.23 ( dd, J = 8.3, 1.0 Hz, 1H, ArH), 7.55-7.62 (m, 3H, 3xArH), 7.95 (dd, J = 8.0, 1.3 Hz, 1H, ArH), 8.12 (d, J =

8.2 Hz, 1H, ArH). Formation of the corresponding imidazolide and immediate reduction of the product as above gave methyl 2- [N- (5'-trifluoromethyl-2'-hydroxymethyl) phenylamino] benzoate (86%), mp (hexane) 86-87 ° 0.

¹ H NMR (0D0l3) δ 2.00 (t, J = 5.6 Hz, 1 H, OH), 3.92 (s, 3 H, 0O20H3), 4.78 (d, J = 5.3 Hz , 2H, OH2), 6.84 (td, J = 7.6, 1.1Hz, 1H, ArH), 7.15 (dd, J = 8.6, 0.8Hz, 1H, ArH), 7.31-7.39 (m, 2H, 2xArH), 7.52 (d, J = 7.7Hz, 1H, ArH), 7.70 (s, 1H, H-6 '), 8.76 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 9.72 (s, 1H, NH).

Oxidation of the product as above gave 2- [N- (5'-trifluoromethyl-2'-formyl) phenylamino] benzoate (85%), mp (MeOH / H2O) 79,5-80,5 ° 0, ¹ H, NMR [(OD3) 2SO] δ 3.86 (s, 3H, OH2OH3), 7.20 (ddd, J = 8.0, 6.2, 2.0 Hz, 1H, ArH), 7.34 (dd , J = 7.5, 0.8Hz, 1H, ArH), 7.60-7.66 (m, 3H, 3xArH), 7.98 (dd, J = 8.0, 1.4Hz , 1H, ArH), 8.09 (d, J = 8.0Hz, 1H, ArH), 10.09 (s, 1H, NH), 11.16 (s, 1H, OHO).

0yklizacja product as above, followed by immediate hydrolysis of the crude 6-trifluorometyloakrydyno-4-carboxylate, gave 6-trifluorometyloakrydyno-4-carboxylic acid (81%), mp (MeOH / H2 O) 244-246 ° 0, ¹ H NMR [ (0D3) 2SO] δ 7.93 (t, J = 7.9 Hz, 1H, H-3), 7.98 (dd, J = 8.9, 1.5 Hz, 1H, ArH), 8.56 (d, J = 8.8 Hz, 1H, ArH), 8.60 (d, J = 8.5 Hz, 1H, ArH), 8.79 (dd, J = 7.0, 1.1 Hz, 1H, ArH), 8.86 (s, 1H, H-5), 9.66 (s, 1H, H-9).

Product activation and coupling as above gave bis [(6-trifluoromethylacridine-4-carboxamido) propyl] methylamine (19) (60%), mp (hexane) 169-171 ° 0.

GB ¹ 193 669 B1 H NMR [(CD3) 2 SO] δ 1.89 (quintet, J = 6, 6 Hz, 4 H, CH2CH2CH2), 2.28 (s, 3 H, NCH 3), 2.66 (t , J = 6.8Hz, 4H, CH2CH3), 3.56 (q, J = 6.1Hz, 4H, NHCH2CH2), 7.60 (dd, J = 8.8, 1.5Hz, 2H, H-7),

7.68 (dd, J = 8.3, 7.2Hz, 2H, H-2), 8.14 (d, J = 8.8Hz, 2H, H-8), 8.23 ( dd, J = 8.4, 1.4 Hz, 2H, ArH),

8.38 (s, 2H, H-5), 8.55 (dd, J = 7.2, 1.5Hz, 2H, ArH), 9.13 (s, 2H, H-9) , 10.78 (t, J = 5.5 Hz, 2H,

CONH). Analysis (C ₃₇ H ₃₁ F ₆ N _s O ₂ ^ 0.5H ₂ O) C, H, N.

Example 36: Preparation of compound 32 of Table I by the method of Scheme 2. Reaction of 2-amino-3,5-dimethylbenzoic acid and methyl iodobenzoate as described (Rewcastle and Denny, Synth. Comm., 1987, 17, 309) and product purification on silica gel, eluting with EtOAc / petroleum ether (1: 4), gave 3,5-dimethyl-2 - [(2-methoxycarbonyl) phenylamino-benzoic acid, (73%), mp. (EtOAc / petroleum ether) 210 -211.5 ° C, ¹ H NMR (CDCl3) 2.07 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 3.97 (s, 3 H, COOCH 3), 6 , 40 (dd, J = 8.3, 0.9Hz, 1H, H-6 '), 6.90-6.94 (m, 1H, H-4'), 7.28-7. 32 (m, 2H, H-5 'and H-4 or H-6), 8.00 (d, J = 1.8 Hz, 1H, H-6 or H-4), 8.03 ( dd, J = 8.0, 1.6 Hz, 1H, H-3 '), 9.45 (br s, 1H, NH).

Reduction of the product as above via the imidazolide gave 2- [N- (4,6-dimethyl-2-hydroxymethyl) phenylamino] benzoate (86%), mp (EtOAc / petroleum ether) 105-106 ° C, ¹ H NMR (CDCl3) δ 1.83 (br s, 1H, OH), 2.13 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.92 (s, 3H, COOCH3), 4.51 (d, J = 12.8Hz, 1H, CH2OH), 4.63 (d, J = 12.8Hz, 1H, CH2OH), 6.22 (d, J = 8 , 3 Hz, 1H, H-3), 6.65 (br t, J = 7.6 Hz, 1H, H-5), 7.07 (br s, 1H, H-3 'or H -5 '), 7.16 (br s, 1H, H-5' or H-3 '), 7.16-7.22 (m, 1H, H-4), 7.95 (dd, J = 8.0, 1.4 Hz, 1H, H-6), 9.01 (br s, 1H, NH).

Oxidation of the product as above gave 2- [N- (4,6-dimethyl-2-formyl) phenylamino] benzoate (95%), mp (EtOAc / petroleum ether) 103-104 ° C, ¹ H NMR (CDCl3 ) δ 2.19 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.95 (s, 3H, COOCH3), 6.31 (dd, J = 8.3, 0.8Hz, 1H, H-3), 6.69-6.73 (m, 1H, H-5), 7.20-7.24 (m, 1H, H-4), 7 , 37 (d, J = 1.6 Hz, 1H, H-3 'or H-5'), 7.60 (d, J = 1.7 Hz, 1H, H-5 'or H-3 '), 7.97 (dd, J = 8.0, 1.6 Hz, 1H, H-6), 9.42 (br s, 1H,

NH), 10.14 (s, 1H, CHO).

Cyclization of the product as above gave crude 5,7-dimetyloakrydyno-4-carboxylate (990), ¹ H NMR (CDCl3) δ 2.53 (s, 3 H, CH3), 2.88 (s, 3 H, CH 3 ), 4.12 (s, 3H, COOCH3), 7.49 (br s,

H, H-6 or H-8), 7.52 (dd, J = 8.5, 7.0 Hz, 1H, H-2), 7.57 (br s, 1H, H-8 or H-6), 8.03 (dd, J = 6.8, 1.4 Hz, 1H, H-1 or H-3), 8.05 (dd, J = 8.5, 1.4 Hz , 1H, H-3 or H-1), 8.61 (s, 1H, H-9). Hydrolysis of the product as above gave acid 5,7-dimetyloakrydyno-4-carboxylic acid (73%), mp (MeOH / TEA / AcOH) 312-315 ° C, ¹ H NMR [(CD3) 2 SO / NaOD] δ 2 49 [s, partially obscured by DMSO, 3H, CH3), 7.39-7.45 (m, 2H, H-1 and H-2), 7.49 (br s, 1H, H-6 or H-8), 7.67 (br s, 1H, H-8 or H-6), 7.85 (dd, J = 7.7, 2.1

Hz, 1H, H-3) and 8.76 (s, 1H, H-9). Analysis (C16H13NO2) C, H, N.

Activation and coupling of the product as above gave bis [(5,7-dimetyloakrydyno-4-carboxamido) -propyl] methylamine (32) as an orange oil (56%), ¹ H NMR (CDCl3) δ 1.94-2.05 (m, 4H, 2xCH2CH2CH2), 2.31 (s, 3H, NCH3), 2.45 (s, 6H, 2xCH3), 2.58 (t, J = 7.4Hz, 4H, 2xCH2NCH3 ), 2.70 (s, 6H, 2xCH3), 3.68 (dd, J = 7.2, 5.7Hz, 4H, 2xCH2NH), 7.32 (br s, 2H, H-6 or H-8) 7.41 (br s, 2 H, H-8 or H-6), 7.57 (dd, J = 8.3, 7.2 Hz, 2 H, H-2), 7 , 96 (dd, J = 8.4, 1.4Hz, 2H, H-1), 8.49 (s, 2H, H-9), 8.89 (dd, J = 7.2, 1.5 Hz, 2H, H-3) and 11.75 (br t, J = 5.3 Hz, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C39H42N5O2 612.3339 (MH ⁺ ), found 612.3330. Analysis (C ₃₉ H _{4 and N 5} O ₂ O, 5 H ₂ O) C, H, N.

Example 37: Preparation of 20 from Table I. Bis (6-fluoro) trihydrochloride (16) (0.52 g, 0.7 mmol) was heated with 40% aqueous dimethylamine (10 ml) in MeOH (10 ml ) in a bomb at 100 ° C for a week. The solvent and excess reagent were evaporated under reduced pressure, ammonia was added and the mixture was extracted with CH2Cl2. Evaporation and chromatography of the residue on alumina, eluting with a gradient of MeOH in CH2Cl2 gave bis [(6- (dimethylamino) acridine-4-carboxamido) propyl] methylamine (20) (84%), melting point (HCl salt with MeOH / EtOAc ) 100 ° C (dec), ¹ H NMR (free base in CDCl3) δ 2.03 (quintet, J = 7.0 Hz, 4 H, 2xCH2CH2CH2), 2.37 (s, 3 H, NCH 3), 2 , 82 (t, J = 7.6 Hz, 4H, 2xCH2NCH3), 2.85 (s, 12H, 2xN (CH3) 2), 3.73 (q, J = 6.1Hz, 4H, 2xCH2NH), 6.54 (d, J = 2.2Hz, 2H, H-5), 6.67 (dd, J = 9.2, 2.4Hz, 2H, H-7), 7 . 31 (d, J = 9.2 Hz, 2H,

PL 193 669 B1

H-8), 7.40 (t, J = 7.6 Hz, 2 H, H-2), 7.86 (dd, J = 8.2, 1.6 Hz, 2 H, H-1) , 8.21 (s, 2H, H-9), 8.81 (dd, J =

7.2, 1.6 Hz, 2H, H-3), 12.15 (t, J = 5.0 Hz, 2H, 2xCONH).

Example 38: Preparation of 38 of Table I. Phenazine-1-carboxylic acid suspension [Rewcastle and Denny, Synth. Comom., 1987, 17, 1171] (1.30 g, 5.8 mmol) in DMF (8 mL) was treated with 1,1'-carbonyldiimidazole (1.13 g, 7.0 mmol), and the mixture was stirred at temperature 45 ° C for 30 minutes. After cooling, the mixture was diluted with CH2Cl2 / petroleum ether (1: 1) to complete the precipitation of the crude imidazolide which was collected, washed with petroleum ether and dried. The crude imidazolide (1.33 g, 4.85 mmol) was added to an ice-cold solution of N, N-bis (3-aminopropyl) methylamine (0.35 g, 2.41 mmol) in THF (15 mL) and the mixture was stirred for a while. at 20 ° C for 4 hours. The volatiles were removed under reduced pressure and the residue was partitioned between CH2Cl2 and aqueous Na2CO3. The organic layer was washed with water, dried and evaporated and the residue was chromatographed on alumina-90. Elution of CH2Cl2 / MeOH (20: 1) followed by recrystallization from EtO-Ac / iPr2O gave bis [(phenazine-1-carboxamido) propyl] -methylamine (38) (1.02 g, 63% from acid), m.p. 153-154 ° C, ¹ H NMR [(CD3) 2 SO] δ 1.87 (quintet, J = 6.5 Hz, 4 H, 2xCH2CH2CH2), 2.27 (s, 3 H, CH3), 2.62 (t, J = 6.7 Hz, 4H, 2xCH2NCH3), 3.53 (q, J = 5.7 Hz, 4H, 2xCH2NH), 7.5-7.8 (m, 4H, ArH) , 7.8-8.1 (m, 6H, ArH), 8.16 (d, J = 8.6Hz, 2H, ArH), 8.47 (d, J = 6.9Hz, 2 H, ArH), 10.14 (t, J = 5.0 Hz, 2H, 2xNH). Treatment with MeOH / EtOAc / HCl (1 eq.) Gave the monohydrochloride salt, m.p. (MeOH / EtOAc) 233-235 ° C. Analysis (C ₃₃ H ₃₁ N ₇ O ₂ 2 HCl 2 0.5 _{H 2} O) C, H, N, Cl.

Example 39: Preparation of compound 39 of Table I. Activation and coupling of phenazine-2-carboxylic acid as above gave bis [(phenazine-2-carboxamido) propyl] methylamine (39) as a yellow solid (88%) temperature mp 196-197,5 ° C, ¹ H NMR (CDCl3) δ 1.90-1.96 (m, 4 H, 2xCH2CH2CH2), 2.34 (s, 3 H, NCH 3), 2.64 (t, J = 6.2Hz, 4H, 2xCH2NCH3), 3.71 (q, J = 6.0Hz, 2H, 2xCH2NH), 7.66 (ddd, J = 8.6, 6.6, 1, 5 Hz, 2 H, H-7 or H-8), 7.72 (ddd, J = 8.7, 6.6, 1.5 Hz, 2 H, H-8 or H-7), 7, 99 (dd, J = 8.7, 1.3 Hz, 2H, H-6 or H-9), 8.12 (dd, J = 8.4, 1.3 Hz, 2H, H-9 or H-6), 8.16, (m, 4H, H-4 and NH), 8.21 (dd, J = 9.1, 1.9Hz, 2H, H-3) and 8.44 (d, J = 1.6 Hz, 2 H, H -1). Analysis (C33H31N7O2) C, H, N;

HRMS (FAB ⁺ ) M / z calcd for C33H32N7O2 558.2617 (MH ⁺ ), found 558.2599.

Example 40: Preparation of compound 40 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 6-Methylphenazine-1-carboxylic acid as above gave bis [(6-methylphenazine-1-carboxamido) propyl] methylamine (40) (47%), m.p. (HCl salt) 228- 230 ° C (MeOH / EtOAc), ¹ H NMR (CDCl3) δ 2.06 (quintet, J = 6.9 Hz, 4 H, 2xCH2CH2CH2), 2.39 (s, 3 H, NCH 3), 2.79 (s, 6H, 2xArCH3), 2.81 (t, J = 7.0Hz, 4H, 2xCH2NCH3), 3.75 (q, J = 6.1Hz, 4H, 2xCH2NH), 7.42 (t, J =

7.8 Hz, 2H, H-8), 7.61 (d, J = 8.8 Hz, 2H, 2xArH), 7.87 (dd, J = 8.5, 7.1 Hz, 4 H, H-3, 2xArH), 8.27 (dd, J = 8.7, 1.5 Hz, 2 H, H-4), 8.88 (dd, J = 7.0, 1.5 Hz , 2H, H -2), 10.93 (br s, 2H, 2xCONH).

Example 41: Preparation of compound 41 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 6-chlorophenazine-1-carboxylic acid as above gave bis [(6-chlorophenazine-1-carboxamido) propyl] methylamine (41) (56%), m.p. (CH2Cl2 / MeOH) 198 -200 ° C, ¹ H NMR (CDCl3) δ 2.01-2.06 (m, 4 H, 2xCH2CH2CH2), 2.37 (s, 3 H, NCH 3), 2.73 (t, J = 7. 2 Hz, 4H, 2xCH2NCH3), 3.72 (q, J = 6.2Hz, 2H, 2xCH2NH), 7.62 (dd, J = 8.7, 7.2Hz, 2H, H- 8), 7.74 (dd, J = 7.2, 1.2Hz, 2H, H-7 or H-9), 7.91 (dd, J = 8.8, 1.2Hz, 2 H, H-9 or H-7), 7.93 (dd, J = 8.7, 7.1 Hz, 2 H, H-3), 8.39 (dd, J = 8.7, 1, 6 Hz, 2 H, H-4), 8.88 (dd, J = 7.1, 1.6 Hz, 2 H, H-2), 10.59 (br t, J = 5.1 Hz, 2H, 2xCONH),

HRMS (FAB ⁺ ) m / z calcd for C33H29C12N7O4 626.1838 (MH ⁺ ), found 618.1840. Analysis (C33H29C12N7O2) C, H, N, Cl)

Example 42: Preparation of compound 42 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 7-Methylphenazine-1-carboxylic acid as above gave bis [(7-methylphenazine-1-carboxamido) propyl] methylamine (42) (63%), m.p. (HCl salt) 213- 215 ° C (MeOH / EtOAc), ¹ H NMR (CDCl3) δ 2.06 (quintet, J = 6.9 Hz, 4 H, 2xCH2CH2CH2), 2.38 (s, 3 H, NCH 3), 2.44 (s, 6H, 2xArCH3), 2.79 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 3.75 (q, J = 6.2Hz, 4H, 2xCH2NH), 7.40 (dd, J = 8.9, 1.6Hz, 2H, H-8), 7.62 (br s, 2H, H-6), 7.77 (d, J = 8.9Hz, 2 H, H-9), 7.86 (dd, J = 8.5, 7.1 Hz, 2 H, H-3), 8.22 (dd, J = 8.6, 1.5 Hz, 2 H, H-4), 8.86 (dd, J = 7.2, 1.5 Hz, 2 H, H-2), 10.85 (t, J = 4.9 Hz, 2H, 2xCONH ). Analysis (C ₃₅ H ₃₅ N ₇ O / HCl) C, H, N, Cl.

PL 193 669 B1

Example 43: Preparation of compound 43 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 7-methoxyphenazine-1-carboxylic acid as above gave bis [(7-methoxyphenazine-1-carboxamido) propyl] methylamine (43) (60%), m.p. (HCl salt) 225- 229 ° C (MeOH / EtOAc), ¹ H NMR (CDCl3) δ 2.03 (quintet, J = 6.9 Hz, 4 H, 2xCH2CH2CH2), 2.37 (s, 3 H, NCH 3) 2, 74 (t, J = 7.2 Hz, 4H, 2xCH2NCH3), 3.73 (q, J = 6.3 Hz, 4H, 2xCH2NH), 3.93 (s, 6H, 2xArOCH3), 7. 10 (d, J = 2.7 Hz, 2H, H-6), 7.28 (dd, J = 9.1, 3.1 Hz, 2H, 2xArH), 7.78 (d, J = 9.5 Hz, 2 H, H-9), 7.83 (dd, J = 8.7, 1.5 Hz, 2 H, H-8), 8.17 (dd, J = 8.6, 1.5 Hz, 2H, 2xArH), 8.81 (J = 7.2, 1.5 Hz, 2H, H-2), 10.77 (t, J = 4.6 Hz, 2H, 2xCONH). Analysis (C ₃₅ H ₃₅ N ₇ O ₄ 2 HCl 3 ₃ H 2 O) C, H, N.

Example 44: Preparation of compound 44 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 7-chlorophenazine-1-carboxylic acid as above gave bis [(7-chlorophenazine-1-carboxamido) propyl] methylamine (44) (71%), m.p. (CH2Cl2 / MeOH) 173 -175 ° C.

¹ H NMR (CDCl3) δ 1.99-2.06 (m, 4 H, CH2CH2CH2), 2.37 (s, 3 H, NCH 3), 2.73 (t, J = 7.2 Hz, 4 H , CH2NCH3), 3.73 (q, J = 6.5, 5.8 Hz, 2H, CH2NH), 7.54 (dd, J = 9.3, 2.4 Hz, 2H, H-8 ), 7.84 (d, J = 9.3Hz, 2H, H-9), 7.90 (d, J = 2.5Hz, 2H, H-6), 7.92 (dd, J = 8.7, 7.1 Hz, 2 H, H-3), 8.20 (dd, J = 8.7, 1.6 Hz, 2 H, H-4), 8.88 (dd, J = 7.1, 1.5 Hz, 2 H, H -2), 10.54 (br t, J = 5.1 Hz, 2 H, 2x CONH).

HRMS (FAB ⁺ ) m / z calcd for C33H29Cl2N7O4 626.1838 (MH ⁺ ), found 618.1844. Analysis (C33H29C12N7O2) C, H, N, Cl.

Example 45: Preparation of compound 45 of Table I. Activation and coupling of the known [Rewcastle and Denny, Synth. Comm., 1987, 17, 1171] 8-Methylphenazine-1-carboxylic acid as above gave bis [(8-methylphenazine-1-carboxamido) propyl] methylamine (45) (76%), m.p. (HCl salt) 215 ° C (dec) (MeOH / EtOAc), ¹ H NMR (CDCl3) δ 2.16 (quintet, J = 6.6 Hz, 4 H, 2xCH2CH2CH2), 2.52 (s, 9 H, NCH3, 2xArCH3), 2.93 (m, 4H, 2xCH2NCH3), 3.76 (q, J = 6.3Hz, 4H, 2xCH2NH), 7.41 (d, J = 8.6Hz, 2H, H-6 ), 7.77 (br s, 2H, H-9), 7.86 (dd, J = 8.5, 7.1Hz, 4H, H-3.7), 8.26 (dd, J = 8.6, 1.5 Hz, 2 H, H-4), 8.87 (dd, J = 7.7, 1.5 Hz, 2H, H-2), 11.00 (br s , 2H, 2xCONH).

Example 46: Preparation of compound 46 of Table I. Activation and coupling of the known [Rewcastle and Denny, Synth. Comm., 1987, 17, 1171] 8-methoxyphenazine-1-carboxylic acid as above gave bis [(8-methoxyphenazine-1-carboxamido) propyl] methylamine (46) (99%), mp 182-186 ° C (dec.) (MeOH / EtOAc), ¹ H NMR (CDCl3) δ 1.92 (m, 4 H, 2xCH2), 2.30 (s, 3 H, NCH3), 2.71 (m, 4 H, 2xCH2), 3.60 (q, J = 6.1 Hz, 4H, 2xCH2NH), 3.85 (s, 6H, 2xArOCH3), 7.06 (s, 2H, H-9), 7, 19 (dd, J = 9.4, 2.4Hz, 2H, H-7), 7.69 (d, J = 9.4Hz, 2H, H-6), 7.80 (dd, J = 8.6, 7.2Hz, 2H, H-3), 8.11 (dd, J = 8.5, 1.4Hz, 2H, H-4), 8.48 (J = 7.1, 1.5 Hz, 2H, H -2), 10.39 (t, J = 5.4 Hz, 2H, 2xCONH). Analysis (C35H35N7O4) C, H, N.

Example 47: Preparation of Compound 47 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 9-Methylphenazine-1-carboxylic acid as above gave bis [(9-methylphenazine-1-carboxamido) propyl] methylamine (47) (82%), melting point (salt

HCl) 262-264 ° C (MeOH / EtOAc), ¹ H NMR (CDCl3) δ 1.99 (quintet, J = 7.3 Hz, 4 H, 2xCH2CH2CH2), 2.32 (s, 3 H, NCH 3) , 2.60 (t, J = 7.4Hz, 4H, 2xCH2NCH3), 2.79 (s, 6H, 2xArCH3), 3.75 (q, J = 6.7Hz, 4H, 2xCH2NH) , 7.56 (d, J = 6.73Hz, 2H, H-8), 7.65 (dd, J = 8.7, 7.2Hz, 2H, H-7), 7.89 (dd, J = 8.7, 7.2 Hz, 2H, H-3), 7.97 (d, J = 8.6 Hz, 2H, H-6), 8.27 (dd, J = 8.7, 1.5 Hz, 2 H, H-4), 8.93 (dd, J = 7.2, 1.5 Hz, 2 H, H-2), 10.94 (br s, 2H, 2xCONH). Analysis (C ₃₅ H ₃₅ N ₇ O / HCl) C, H, N, Cl.

Example 48: Preparation of compound 48 of Table I. Activation and coupling of 9-methylphenazine-1-carboxylic acid as above followed by coupling with 1,4-bis (aminopropyl) piperazine gave the crude product which was dissolved in MeOH / AcOH , treated with activated carbon / Celite and filtered, then basified with Et3N to give bis [(9-methylphenazine-1-carboxamido) propyl] -1,4-piperazine (48) (45%) as free base, mp. (MeOH) 252,253 ° C, ¹ H NMR (hydrochloride salt in D 2 O) δ 2.07 (quintet, J = 7.5 Hz, 4 H, 2xCH2CH2CH2), 2.89 (s, 6 H, 2xCH3), 3.10 (t, J = 7.0 Hz, 6H, 3xCH2), 3.29 (br s, 6H, 3xCH2), 3.64 (t, J - 6.7 Hz, 6H, 3xCH2), 7.927.98 (m, 4H, 4xArH), 8.11 (dd, J = 9.6, 7.2Hz, 2H, 2xArH), 8.15 (d, J = 8.4Hz, 2H, 2xArH), 8, 45 (dd, J = 8.7, 1.3 Hz, 2H, 2xArH), 8.69 (dd, J = 7.1, 1.3 Hz, 2H, H-2). Analysis (C ₃₈ H ₄₀ N ₈ O ₂ O, 5 H ₂ O) C, H, N.

Example 49. Preparation of compound 49 of Table I. Activation and coupling of 9-methylphenazine-1-carboxylic acid as above followed by coupling with ethylene triamine gave su26

The product was dissolved in MeOH / AcOH, treated with activated carbon / Celite and filtered, then basified with Et 3 N to give bis [(9-methylphenazine-1-carboxamido) ethyl] -1,4-ethylenediamine (49) ( 33%) mp (HCl salt from MeOH / EtOAc) 281 ° C (dec), ¹ H NMR (hydrochloride salt in D 2 O) δ 2.89 (s, 6 H, 2xCH3), 3.38 (m, 8 H, 4xCH2), 3.90 (q, J = 6.6, 4H, 2xCH2), 7.90 (m, 4H, 4xArH), 8.07 (dd, J = 8.6, 7.2Hz , 2H, H-3), 8.13 (d, J = 8.2 Hz, 2H, 2xArH), 8.44 (dd, J = 8.7, 1.4 Hz, 2H, 2xArH), 8.71 (dd, J = 7.1, 1.4 Hz, 2H, H -2). HRMS analysis (FAB ⁺ ) m / z calcd for C34H34N8O2 586.61, found 587.29.

Example 50. Preparation of compound 50 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987,30,843] 9-methoxyphenazine-1-carboxylic acid as above gave bis [(9-methoxyphenazine-1-carboxamido) propyl] methylamine (50) (86%), m.p. (CH2Cl2 / MeOH) 220 -222 ° C, ¹ H NMR (CDCl3) δ 1.99-2.05 (m, 4 H, 2xCH2CH2CH2), 2.39 (s, 3 H, NCH 3), 2.73 (t, J = 7. 6 Hz, 4H, 2xCH2NCH3), 3.66 (q, J = 6.0 Hz, 2H, 2xCH2NH), 3.90 (s, 6H, OCH3), 6.60 (dd, J = 6, 7.1.9Hz, 2H, H-6 or H-8), 7.32-7.38 (m, 4H, H-7 and H-8 or H-6), 7.84 (dd , J = 8.7, 7.2 Hz, 2H, H-3), 8.11 (dd, J = 8.7, 1.5 Hz, 2H, H-4), 8.83 (dd , J = 7.1, 1.5 Hz, 2 H, H -2), 11.12 (br t, J = 4.7 Hz, 2 H, NH).

HRMS (FAB ⁺ ) m / z calcd for C35H35N7O4 618.2829 (MH ⁺ ), found 618.2847. Analysis (C35H35N7O4) C, H, N.

Example 51. Preparation of compound 51 of Table I. Activation and coupling of the known [Atwell et al., European Patent Application EP 172744, February 1986; Chem. Abstr. 1986, 105, 97496p] 9-fenoksyfenazyno-1-carboxylic acid as above gave bis [(9-fenoksyfenazyno-1-carboxamido) propyl] methylamine (51) as an orange oil (51%), ¹ H NMR (CDCl3) δ 1 , 69-1.73 (m, 4H, 2xCH2CH2CH2), 1.97 (s, 3H, NCH3), 2.31 (t, J = 7.3Hz, 4H, 2xCH2NCH3), 3.43 ( q, J = 6.4Hz, 2H, 2xCH2NH), 7.11-7.14 (m, 6H, H-2 ', H-6' and H-6 or H-8), 7.18 (t, J = 7.5 Hz, 2 H, H-4 '), 7.39 (t, J = 7.5 Hz, 4 H, H-3' and H-5 '), 7.69 ( dd, J = 8.7, 7.6 Hz, 2H, H-7), 7.89 (dd, J = 8.7, 1.0 Hz, 2H, H-3, H-8 or H -6), 8.26 (dd, J = 8.7, 1.5 Hz, 2H, H-4), 8.90 (dd, J = 7.1,

1.5 Hz, 2H, H -2) and 10.98 (br t, J = 5.2 Hz, 2H, 2xCONH);

HRMS (FAB ⁺ ) m / z calcd for C45H40N7O4 742.3142 (MH ⁺ ), found 742.3147.

Example 52: Preparation of compound 52 of Table I. Activation and coupling of the known [Rewcastle et al., Synth. Comm., 1987, 17, 1171] 9-fluoro-phenazine-1-carboxylic acid as above gave bis [(9-fluorophenazine-1-carboxamido) propyl] methylamine (52) (870), m.p. (CH2Cl2 / MeOH) 186- 187 ° C, ¹ H NMR (CDCl3) δ 2.00-2.04 (m, 4 H, CH2CH2CH2), 2.36 (s, 3 H, NCH3), 2.72 (t, J = 7.4 Hz, 4H, CH2NCH3), 3.73 (q, J = 6.2Hz, 2H, CH2NH), 7.30-7.35 (m, 2H, H-7 or H-8), 7 , 54-7.60 (m, 2H, H-8 or H-7), 7.84 (d, J = 9.0Hz, 2H, H-6), 7.94 (dd, J = 8.7, 7.0Hz, 2H, H-3), 8.25 (dd, J = 8.7, 1.5Hz, 2H, H-4), 8.95 (dd, J = 7.0, 1.5 Hz, 2H, H -2), 10.94 (br t, J = 5.0 Hz, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C33H29F2N7O4 594.2429 (MH ⁺ ), found 594.2403. Analysis (C ₃₃ H _{2 9} F 2 N _{7 O 2} O, 5 H 2 O) c, h, n.

Example 53: Preparation of compound 53 of Table I. Activation and coupling of the known [Rewcastle et al., J. Med. Chem., 1987, 30, 843] 9-chlorophenazine-1-carboxylic acid as above gave bis [(9-chlorophenazine-1-carboxamido) propyl] methylamine (53) (860), m.p. (CH2Cl2 / MeOH) 169- 171.5 ° C, ¹ H NMR (CDCl3) 1.99-2.03 (m, 4 H, 2xCH2CH2CH2), 2.32 (s, 3 H, NCH 3), 2.62 (t, J = 7. 4 Hz, 4H, 2xCH2NCH3), 3.70 (q, J = 6.2Hz, 2H, CH2NH), 7.64 (dd, J = 8.8, 7.4Hz, 2H, H- 7), 7.80 (dd,

J = 7.2, 1.0 Hz, 2 H, H-6 or H-8), 7.95 (dd, J = 8.7, 7.2 Hz, 2 H, H-3), 8, 01 (dd, J = 8.7, 1.0 Hz, 2H, H-8 or H-6), 8.27 (dd, J = 8.7, 1.5 Hz, 2H, H-4 ), 8.99 (dd, J = 7.2,1.5 Hz, 2H, H -2), 10.94 (br t,

J = 5.0 Hz, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C33H29Cl2N7O4 626.1838 (MH ⁺ ), found 618.1848. Analysis (C33H29C12N7O2) C, H, N.

Example 54: Preparation of Compound 54 of Table I. 9-Fluoro-phenazine-1-carboxylic acid solution [Rewcastle et al., J. Synth. Comm. 1987, 17, 1171] (200 mg, 0.8 mmol) in Me2NH (40% in water, 20 ml) was heated at 100 ° C in a bomb for 3 hours. A strong purple solution resulted, diluted with water and then neutralized with AcOH. The aqueous solution was then extracted with CHCl3 (3 x 50 mL) until all staining was removed. The organic layer was washed with water (1x 150 mL) then dried over Na2SO4 and the solvent removed in vacuo. The resulting purple solid was dissolved in a minimal amount of CH2Cl2 and petroleum ether was added

GB 193 669 B1 to effect crystallization to yield 9- (dimethylamino) fenazyno-1-carboxylic acid as dark purple needles (210 g, 95%), m.p. 186-187,5 0 °, ¹ H NMR (0D0l3) δ 3 16 [s, 6 H, N (OH3) 2], 7.26 (dd, J = 6.8, 1.8 Hz, 1H, H-6 or H-8), 7.81-7.88 (m, 2H, H-7 and H-8 or H-6), 8.01 (dd, J = 8.7, 7.0 Hz, 1H, H-3), 8.48 (dd, J = 8.7, 1.2 Hz, 1H, H-4)

8.91 (dd, J = 7.0, 1.3 Hz, 1H, H -2). Analysis (015H13N3O2) 0, H, N.

Product activation and coupling as above gave bis [((9-dimethylamino) phenazine-1-carboxamido) propyl] methylamine (54) as a reddish purple oil (78%).

¹ H NMR (0D0l3) δ 1.91-2.00 (m, 4 H, 2x0H20H20H2), 2.29 (s, 3 H, N0H3), 2.57 (t, J = 7.3 Hz, 4 H , OH2N0H3), 3.05 (s, 12H, 2xN (OH3) 2), 3.68 (q, J = 6.5Hz, 2H, OH2NH), 7.07 (dd, J = 7.2 1.3 Hz

H, H-6 or H-8), 7.65 (dd, J = 8.7, 7.3 Hz, 2 H, H-7), 7.70 (dd, J = 8.7, 1, 3 Hz, 2H, H-8 or H-6), 7.90 (dd, J = 8.6, 7.1 Hz, 2H, H-3), 8.27 (dd, J = 8, 6, 1.4 Hz, 2 H, H-4), 8.87 (dd, J = 7.1, 1.4 Hz, 2 H, H-2) and 10.99 (br t, J = 5 , 1 Hz, 2H, 2xOONH);

HRMS (FAB ⁺ ) m / z calcd for 037H42N9O2 644.3461 (MH ⁺ ), found 544.3485.

Example 55: Preparation of compound 55 from table I. The bis (5-fluoro) analog (11) was heated at 100 ° 0 in excess of 40% aqueous dimethylamine / MeOH for 8 weeks in a pressure reactor, the solvents were then removed by evaporation , and the residue was chromatographed on alumina to give bis [3- (5- (dimethylamino) acridine-4-carboxamido) propyl] methylamine (55) (60%) as a foam, ¹ H NMR (0D0l3) δ 1.97 ( quintet, J = 7.3Hz, 4H, 2xOH20H20H2), 2.30 (s, 3H, NOH3), 2.59 (t, J = 7.3Hz, 4H, OH2N (OH3) OH2), 3.01 (s, 12H, 2xN (OH3) 2), 3.68 (q, J = 6.7 Hz, 4H, 2xOH2NH), 7.12 (dd, J = 7.2, 0.9 Hz, 2H, H-6), 7.39 (dd, J = 8.4, 7.3Hz, 2H, H-7), 7.51 (dd, J = 8.2, 0.8 Hz, 2H, H-8), 7.62 (dd, J = 8.3, 7.2Hz, 2H, H-2), 8.04 (dd, J = 8.4, 1.4 Hz, 2H, H-1), 8.70 (s, 2H, H-9), 8.91 (dd, J = 7.1, 1.5Hz, 2H, H-3), 11 , 94 (br s, 2H, 2xOQNH). Analysis (C ₃₉ H ₄₃ N ₇ O ₂ ^ H ₂ O) 0, H.

Example 56: Preparation of Compound 56 of Table I. The bis (7-fluoro) analog (27) was heated at 100 ° 0 in excess of 40% aqueous dimethylamine / MeOH for 6 weeks in a pressure reactor, the solvents were then removed by evaporation , and the residue was chromatographed on alumina to give bis [3- (7- (dimethylamino) acridine-4-carboxamido) propyl] methylamine (56) (89%) as a foam, ¹ H NMR (0D0l3) δ 2.08 ( quintet, J = 7.0 Hz, 4H, 2xOH20H20H2), 2.40 (s, 3H, NOH3), 2.86 (t, J = 7.6 Hz, 4H, OH2N (OH3) OH2), 2.99 (s, 12H, 2xN (OH3) 2), 3.75 (q, J = 6.1Hz, 4H, 2xOH2NH), 6.30 (d, J = 2.8Hz, 2H , H-8), 7.18 (dd, J = 9.5, 2.8 Hz, 2 H, H-6), 7.44 (dd, J = 8.2, 7.2 Hz, 2 H , H-2), 7.67 (d, J = 9.5 Hz, 2 H, H-5), 7.82 (dd, J = 8.5, 1.4 Hz, 2 H, H-1 ), 8.13 (s, 2H, H-9), 8.69 (dd, J = 7.1, 1.5Hz, 2H, H-3), 11.84 (t, J = 5 (0 Hz, 2H, 2xCONH). Analysis (C ₃₉ H ₄₃ N ₇ O / H ₂ O) 0, H, N.

Example 57: Preparation of Compound 57 of Table I by the Method of Scheme 1. Reaction of 2,5-dimethylaniline and 2-iodoisophthalic acid under the conditions described in Example 1 gave crude N- (2,5-dimethylphenyl) isophthalic acid. It was cyclized directly with PPA to give 5,8-dimethylacridone-4-carboxylic acid (46% total): mp (MeOH / H20) 343346 ° 0;

¹ H NMR [(0D3) 2 SO] δ 2.87 (s, 6 H, 2x0H3), 6.98 (d, J = 7.3 Hz, 1 H, H-6), 7.33 (t, J = 7.7 Hz, 1H, H-2), 7.51 (d, J = 7.5 Hz, 1H, H-7), 8.41 (dd, J = 7.6, 1.6 Hz, 1H, H-1), 8.46 (dd, J = 7.9, 1.6 Hz, 1H, H-3), 12.00 (br s, 1H, NH), 13, 93 (br s, 1H, OH). Analysis (016H13NO3) 0, H, N.

Reduction of the 5,8-dimethylacridone-4-carboxylic acid as above gave 5,8-dimethylacridine-4-carboxylic acid (82%): mp (MeOH / H20) 239-241 ° 0;

¹ H NMR [(0D3) 2 SO] δ 2.78 (s, 3H, 0H3), 2.83 (s, 3H, 0H3), 7.50 (d, J = 6.7 Hz, 1 H, H-6), 7.81 (d, J = 7.0 Hz, 1H, H-7), 7.88 (dd, J = 8.3, 7.2 Hz, 1H, H-2) , 8.62 (dd, J = 8.4, 1.4 Hz, 1H, H-1), 8.76 (dd, J = 7.0, 1.4 Hz, 1H, H-3) , 8.61 (s, 1H, H-9) 17.48 (s, 1H, OH). Analysis (016H13NO2) O, H, N.

Activation and coupling of 5,8-dimethylacridine-4-carboxylic acid as above gave bis- [3- (5,8-dimethylacridine-4-carboxamido) propyl] methylamine (57) (79%), m.p. (OH2012 / hexane) 119-124 ° 0, ¹ H NMR (0D0l3) δ 2.00 (quintet, J = 7.3 Hz, 4 H, 2x0H20H20H2), 2.31 (s, 3 H, N0H3), 2.60 (t, J = 7.4Hz, 4H, OH2N (OH3) OH2), 2.70 (s, 6H, 2xOH3), 2.73 (s, 6H, 2xOH3), 3.70 (q, J = 6 , 7Hz, 4H, 2xOH2NH), 7.16 (d, J = 7.1Hz, 2H, H-6), 7.40 (d, J = 6.8Hz, 2H, H-7 ), 7.61 (dd, J = 8.1, 7.3 Hz, 2 H, H-2), 8.06 (dd, J = 8.3, 1.4 Hz, 2 H, H-1 ), 8.81 (s, 2 H, H-9), 8.93 (dd, J = 7.1, 1.5 Hz, 2 H, H-3), 11.81 (br s, 2 H , 2x0ONH). Analysis (039H41N5O2) 0, H, N.

Example 58: Preparation of compound 58 of Table I by the method of Scheme 1. Reaction of 3-methylanthranilic acid and 2-bromo-4-methylbenzoic acid under the conditions described

Example 1 gave crude N- (2-methyl-6-carboxyphenyl) -4-methylanthranilic acid. This was cyclized in PPA as above to give 1,5-dimethylacridone-4-carboxylic acid (49% total), mp (MeOH) 317-318 ° C;

¹ H NMR [(CD3) 2 SO] δ 2.51 (s, 3 H, CH3), 2.91 (s, 3 H, CH3), 7.07 (d, J = 8.1 Hz, 1 H, H-2), 7.20 (t, J = 7.0 Hz, 1H, H-7), 7.51 (d, J = 7.0 Hz, 1H, H-6), 8.05 (d, J = 7.7Hz, 1H, H-3), 8.26 (d, J = 7.8Hz, 1H, H-8), 12.45 (br s, 1H, CO2H ). Analysis (C16H13NO3) C, H, N.

Reduction of 1,5-dimethylacridone-4-carboxylic acid as above gave 1,5-dimethylacridine-4-carboxylic acid (98%), mp (MeOH) 267 ° C (decomposition);

¹ H NMR [(CD3) 2 SO] δ 2.83 (s, 3 H, CH3), 2.93 (s, 3 H, CH3), 7.70 (dd, J = 8.1, 7.2 Hz , 2 H, H-2.7), 7.95 (d, J = 6.7 Hz, 1H, H-6), 8.25 (d, J = 8.4 Hz, 1H, H- 8), 8.67 (d, J = 7.3Hz, 1H, H-3), 9.63 (s, 1H, H-9), 17.55 (s, 1H, CO2H). Analysis (C16H13NO2) C, H, N.

Activation and coupling of 1,5-dimethylacridine-4-carboxylic acid as above gave bis- [3- (1,5-dimethylacridine-4-carboxamido) propyl] methylamine (58) (82%), m.p. (CH2Cl2 / hexane) 110-116 ° C (decomp.);

¹ H NMR (CDCl3) δ 2.01 (quintet, J = 6.9 Hz, 4 H, 2xCH2CH2CH2), 2.34 (s, 3 H, NCH 3), 2.64 (br t, 4 H, CH 2 N ( CH3) NCH2), 2.77 (s, 12H, 4xCH3), 3.69 (q, J = 6.7Hz, 4H, 2xCH2NH), 7.36 (dd, J = 8.4,

6.9 Hz, 2 H, H-7), 7.42 (dd, J = 7.2, 0.8 Hz, 2 H, H-6), 7.52 (d, J = 6.8 Hz , 2H, H-8), 7.75 (d, J = 8.4Hz, 2H, H-2), 8.80 (s, 2H, H-9), 8.8 (d, J = 8.6 Hz, 2H, H-3), 11.80 (br S, 2H, 2xCONH). Analysis (C ₃₉ H ₄₁ N 50 / 2H ₂ O) C, H, N.

Example 59: Preparation of compound 59 of Table I by the method of Scheme 1. Reaction of 2-methyl-5-chloroaniline and 2-iodoisophthalic acid under the conditions described in Example 1 gave crude N- (2-methyl-5-chlorophenyl) acid isophthalic. It was cyclized directly with PPA to give 8-chloro-5-methylacridone-4-carboxylic acid (51% total): mp (MeOH) 325-330 ° C;

¹ H NMR [(CD3) 2 O] δ 2.50 (s, 3 H, CH 3, covered by DMSO peak), 7.81 (d, J = 7.2 Hz, 1 H, H-6), 7.38 (t, J = 7.8Hz, 1H, H-2), 7.61 (d, J = 7.7Hz, 1H, H-7), 8.43-8.48 (m, 2 H, H-1.3), 12.18 (br s, 1H, NH), 14.10 (s, 1H, CO2H). Analysis (C15H10ClNO3) C, H, N.

Reduction of 8-chloro-5-methylacridone-4-carboxylic acid as above left 8-chloro-5-methylacridine-4-carboxylic acid (84%): mp (MeOH) 259-260 ° C;

¹ H NMR [(CD3) 2 SO] δ 2.81 (s, 3 H, CH3), 7,86-7,95 (m, 3H, H-1,2,3), 8.74 (d, J = 8.4 Hz, 1H, H-6), 8.80 (d, J = 7.0 Hz, 1H, H-7), 9.70 (s, 1H, H-9), 16.83 (s, 1H, CO2H). Analysis (C15H10ClNO2)

C, H, N.

Activation and coupling of 8-chloro-5-methylacridine-4-carboxylic acid as above gave bis- [3- (8-chloro-5-methyl-acridine-4-carboxamido) propyl] methylamine (59) (810): m.p. (CH2Cl2 / hexane) 212-215 ° C;

¹ H NMR (CDCl3) δ 1.98 (quintet, J = 7.3 Hz, 4 H, 2xCH2CH2CH2), 2.02 (s, 3 H, NCH3), 2.60 (t, J = 7.4 Hz , 4 H, CH2N (CH3) CH2), 2.67 (s, 6H, 2xCH3), 3.70 (q, 4H, 2xCH2NH), 7.28 (dd, J = 7.7, 0.9 Hz, 2H, H-7), 7.32 (d, J = 7.4Hz, 2H, H-6), 7.65 (dd, J = 8.3, 7.2Hz, 2H , H-2), 8.07 (dd, J = 8.6, 1.5 Hz, 2 H, H-1), 8.96 (dd, J = 7.2, 1.5 Hz, 2 H , H-3), 9.01 (s, 2H, H-9), 11.41 (t, J = 5.3Hz, 2H,

2xCONH). Analysis (C ₃₇ H ₃₅ Cl ₂ N ₂ O ₅ O.5 H ₂ O) C, H, N, Cl.

Example 60: Preparation of compound 60 in Table I by the method of Scheme 2.

A mixture of 3-methylanthranilic acid (7.6 g, 50 mmol), methyl 4-chloro-2-iodobenzoate (19.2 g, 65 mmol), Cu and CuI (catalytic) in 2.3 dibutanol (20 ml) was heated with benzene (30 mL) in an oil bath. After distilling the benzene, N-ethylmorpholine (50 ml) was added and the stirred mixture was heated at 110 ° C for 18 hours, then diluted with dilute HCl, extracted into EtOAc and filtered to remove the Cu salt. The organic layer was separated and extracted into dilute NH4OH, then the ammonium salt of the product precipitated. This was collected and stirred in dilute HCl, and the mixture was filtered and washed with water to give 2 - [[(5-chloro-2-methoxycarbonyl) phenyl] amino] -3-methylbenzoic acid (6.6 g, 41%): m.p. (MeOH) 187-188.5 ° C;

¹ H NMR [(CD3) 2 SO] δ 2.10 (s, 3 H, CH), 3.87 (s, 3 H, OCH3), 6.12 (d, J = 2.0 Hz, 1 H, H-6 '), 6.79 (dd, J = 8.6, 2.0 Hz, 1H, H-4'), 7.29 (t, J = 7.6 Hz, 1H, H- 5), 7.52 (d, J = 7.4Hz, 1H, H-4), 7.74 (d, J = 7.4Hz, 1H, H-6), 7.89 (d , J = 8.5 Hz, 1H, H-3 '), 9.90 (br s, 1H, NH). Analysis (C16H14ClNO4) C, H, N, Cl.

A solution of 2 - [[(5-chloro-2-methoxycarbonyl) phenyl] amino] -3-methylbenzoic acid (6.0 g, 18.8 mmol) in dry THF (100 mL) was treated with CDI (6.0 g, 37.6 mmol) at 20 ° C for

Hours, and the solution was then added dropwise to a suspension of NaBH ₄ (0.69 g, 5 equiv) in H ₂ O (50 mL). When the reaction was complete (30 minutes as observed by TLC), the mixture was quenched with dilute HCl and extracted with CH ₂ Cl ₂ . Layer was filtered CH ₂ Cl ₂ dried to give the crude product which was chromatographed on silica gel, eluting with a gradient of 1% MeOH in CH2Cl2 to give 4-chloro-2- [N- (2-hydroxymethyl-6-methyl) phenylamino] benzoate carboxylate (1.0 g, 170), mp (CH2Cl2 / hexane) 114-115 ° C, ¹ H NMR (CDCl3) δ 1.78 (br s, 1H, OH), 2.18 (s, 3 H, CH3), 3.92 (s, 3H, CO2CH3), 4.54 (dd, J = 12.8, 4.3Hz, 1H, CHOH), 4.67 (dd, J = 12, 8, 4.3Hz, 1H, CHOH), 6.01 (d, J = 2.0Hz, 1H, H-3), 6.63 (dd, J = 8.3, 2.0Hz , 1H, H-5), 7.24-7.29 (m, 2H, 2ArH), 7.35-7.39 (m, 1H, ArH), 7.89 (d, J = 8 , 6 Hz, 1H, H-6), 9.22 (s, 1H, NH). Analysis (C16H16ClNO3) C, H, N.

A solution of methyl 4-chloro-2- [N- (2-hydroxymethyl-6-methyl) phenylamino] benzoate (0.72 g, 2.35 mmol) in EtOAc (100 mL) was refluxed for 7 hours with MnO2 ( 1 g). The mixture was filtered through Celite to remove the Mn residue, the solvent was evaporated and the residue was filtered through a column of silica gel in CH2Cl2 to give methyl 4-chloro-2- [N- (2-formyl-6-methyl) phenylamino] benzoate (0.7 g, 98%): mp (MeOH / H2 O) 81-82 ° C, ¹ H NMR (CDCl3) δ 2.23 (s, 3 H, CH3), 3.95 (s, 1 H, CO2CH3), 6, 27 (d, J = 2.0 Hz, 1H, H-3), 6.70 (dd, J = 8.7, 2.0 Hz, 1H, H-5), 7.37 (t, J = 7.6 Hz, 1H, H-4 '), 7.58 (d, J = 7.9 Hz, 1H, H-5'), 7.81 (dd, J = 7.7, 1.3 Hz, 1H, H-3 '), 7.92 (d, J = 8.6 Hz, 1H, H-6), 9.68 (br s, 1H, NH), 10, 15 (s, 1H, CHO).

Analysis for methyl 4-chloro-2- [N- (2-formyl-6-methyl) phenylamino] -benzoate. Analysis (C16H14ClNO3) C, H, N.

A solution of 4-chloro-2- [N- (2-formyl-6-methyl) phenylamino] benzoate (0.65 g, 2.1 mmol) in trifluoroacetic acid (8 ml) was stirred at 40 ° C for 4 hours under nitrogen. Excess reagent was removed under reduced pressure at 40 ° C, the residue was suspended in 2N NaOH (25 mL) and EtOH (18 mL) and heated for 1 hour until a clear solution was obtained. The cooled reaction mixture was neutralized with AcOH, and the resulting precipitate was collected, washed with water and dried to give 1-chloro-5-methylacridine-4-carboxylic acid (0.56 g, 96%), mp (MeOH / H2O) 260 ° C ( schedule);

¹ H NMR (CDCl3) δ 2.93 (s, 3 H, CH3), 7.64 (dd, J - 8.4, 7.9 Hz, 1 H, H-7), 7,83-7, 86 (m, 2H, H-2 & H-6 or H-8), 8.08 (d, J = 8.6 Hz, 1H, H-8 or H-6), 8.84 (d , J = 7.8Hz, 1H, H-3), 9.4 (s, 1H, H-9), 17.26 (s, 1H, CO2H). Analysis (C15H10ClNO2) C, H, N.

Activation and coupling of 1-chloro-5-methylacridine-4-carboxylic acid as above gave bis [3- (1-chloro-5-methylacridine-4-carboxamido) propyl] methylamine (60) (84%), m.p. (CH2Cl2 / hexane) to 156-158,5 ° C, ¹ H NMR (CDCl3) δ 1.85 (quintet, J = 7.2 Hz, 4 H, 2xCH2CH2CH2), 2.32 (s, 3 H, NCH 3), 2 , 60 (t, 4H, CH2N (CH3) CH2), 2.74 (s, 6H, 2xCH3), 3.68 (q, J = 6.7Hz, 4H, 2xCH2NH), 7.38 ( dd, J = 8.3, 6.8 Hz, 2H, H-7), 7.52 (d, J = 6.8 Hz, 2H, H-6), 7.65 (d, J = 8.0 Hz, 2H, H-2), 7.76 (d, J = 8.5 Hz, 2H, H-8), 8.80 (d, J = 8.0 Hz, 2H, H-3), 9.04 (s, 2H, H-9), 11.50 (br s, 2H, 2xCONH). Analysis for bis [3- (1-chloro-5-methylacridine-4-carboxamido) propyl] methylamine (60). Analysis: (C37H35Cl2N5O2) C, H, N, Cl.

Example 61: Preparation of compound 61 of Table I. Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 3-methylphenazine-1-carboxylic acid gave bis [2- (3-methylphenazine-1-carboxamido) propyl] methylamine (61) as a yellow solid (84%), mp 75-78 ° C (CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 2.03 (quintet, J = 7.0 Hz, 4 H, 2xCH2CH2CH2), 2.37 (s, 3 H, NCH3), 2.67 ( d, J = 0.9Hz, 6H, 2xCH3), 2.73 (t, J = 7.2Hz, 4H, CH2N (CH3) CH2), 3.73 (q, J = 6.3Hz , 2H, 2xCH2NH), 7.62-7.70 (m, 4H, H-7 and H-8), 7.98-8.03 (m, 6H, H-6, H-9 and H-2 or H-4), 8.73 (d, J = 2.1 Hz, 2 H, H-2) and 10.88 (br t, J = 5.2 Hz, 2H, 2xCONH),

HRMS (FAB ⁺ ) m / z calcd for C35H35N7O2 586.2930 (MH ⁺ ), found 586.2931. Analysis (C35H35N7O2 ^ H2O) C, H, N.

Example 62: Preparation of compound 62 of Table I. Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 3-chlorophenazine-1-carboxylic acid gave bis [(3-chlorophenazine-1-carboxamido) propyl] methylamine (62) as a yellow solid (76%), mp 169-170 ° C (CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 2.02 (quintet, J = 6, 9 Hz, 4 H, 2xCH2CH2CH2), 2.36 (s, 3 H, NCH3), 2.72 (t, J = 7.3Hz, 4H, 2xCH2NCH3), 3.71 (q, J = 6.3Hz, 2H, 2xCH2NH), 7.69-7.76 (m, 4H, H-7 and H -8), 7.9430

PL 193 669 B1

8.00 (m, 4H, H-6 and H-9), 8.20 (d, J = 2.5Hz, 2H, H-4), 8.74 (d, J = 2.5 Hz, 2H, H -2) and 10.65 (br t, J =

5.2 Hz, 2H, 2xCONH),

HRMS (FAB ⁺⁾ m / z calcd for C33H29 Cl2N7O2 ³⁵ 626.1838 (MH ^+), found 626.1824. Analysis C ₃₃ H ₂₉ Cl ₂ N ₇ O ₂ ^ H ₂ O) C, H, N.

Example 63: Preparation of compound 63 of Table I. Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 2-chlorophenazine-1-carboxylic acid gave bis [3- (2-chlorophenazine-1-carboxamido) propyl] methylamine (63) as a yellow solid (45%), mp 206-207 ° C ; CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 1.83 (quintet, J = 6.0 Hz, 4 H, 2xCH2CH2CH2), 2.17 (s, 3 H, NCH3), 2.72 (t , J = 6.1Hz, 4H, CH2N (CH3) CH2), 3.67 (q, J = 6.0Hz, 2H, 2xCH2NH), 7.03 (br t, J = 5.9Hz , 2H, 2xCONH), 7.47 (d, J = 9.4Hz, 2H, H-3 or H-4), 7.60-7.68 (m, 4H, H-7 and H -8), 7.89 (d, J = 9.3 Hz, 2 H, H-4 or H-3) 7.91-7.97 (m, 4 H, H-6 and H-9);

HRMS (FAB ⁺⁾ m / z calcd for C33H29 Cl2N7O2 ³⁵ 626.1838 (MH ^+), found 626.1854. Analysis (C33H29Cl2N7O2) C, H, N.

Example 64: Preparation of compound 64 of Table I. Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987, 30, 843] 8-chlorophenazine-1-carboxylic acid gave bis [3- (8-chlorophenazine-1-carboxamido) propyl] methylamine (64) as a pale yellow solid (85%) mp 210-212 ° C ( CH2Cl2 / n-hexane).

¹ H NMR (CDCl3) δ 2.04 (quintet, J = 7.0 Hz, 4 H, 2xCH2CH2CH2), 2.39 (s, 3 H, NCH 3), 2.73 (t, J = 7.2 Hz , 4 H, CH2N (CH3) CH2), 3.74 (q, J = 6.3Hz, 4H, 2xCH2NH), 7.56 (dd, J - 9.2, 2.4Hz, 2H, H-7), 7.92 (dd, J = 8.7, 7.2 Hz, 2 H, H-3), 7.98 (d, J - 9.2, 2 H, H-6), 8.03 (d, J = 2.2Hz, 2H, H-9), 8.26 (dd, J = 8.7, 1.5Hz, 2H, H-4), 8.92 ( dd, J = 7.2, 1.5 Hz, 2H, H -2) and 10.64 (br t, J = 5.2 Hz, 2H, 2xCONH);

HRMS (FAB ⁺⁾ m / z calcd for C33H30 Cl2N7O2 ³⁵ 626.1838 (MH ^+), found 626.1860. Analysis (C33H30Cl2N7O2) C, H, N, Cl.

Example 65: Preparation of Compound 65 of Table I. Reaction of 2-bromo-3-nitrobenzoic acid and 2,5-xylidine gave 2- (2,5-dimethylphenylamino) -3-nitrobenzoic acid (65%): melting point (benzene / acetone) 215-217 ° C, ¹ H NMR [(CD3) 2 SO] δ 2.10 (s, 3 H, CH3), 2.23 (s, 3 H, CH3), 6.53 (s , 1H, H-6 '), 6.79 (d, J = 7.4Hz, 1H, H-4'), 7.02 (t, J = 8.0Hz, 1H, H-5 ), 7.11 (d, J = 7.7Hz, 1H, H-3 '), 8.03 (dd, J = 8.1, 1.4Hz, 1H, H-6), 8 , 22 (dd, J = 7.7, 1.5Hz, 1H, H-4), 9.84 (br s, 1H, NH), 13.8 (br s, 1H, CO2H). Analysis (C15H14N2O4) C, H, N.

Reductive ring closure of the above acid NaOC2H5 / NaBH4 gave 6,9-dimetylofenazyno acid-1-carboxylic acid (64%), mp (MeOH) 246-247 ° C, ¹ H NMR [(CD3) 2 SO] δ 2.78 (s , 3 H, CH3), 2.83 (s, 3 H, CH3), 7.80 (d, J = 7.0 Hz, 1H, H-7 or H-8), 7.84 (s, d, J = 7.0Hz, 1H, H-7 or H-8), 8.12 (dd, J = 8.5, 7.2Hz, 1H, H-3), 8.56 ( d, J = 8.7 Hz, 1 H, H-4), 8.66 (d, J = 7.0 Hz, 1 H, H -2), 15.24 (br s, 1H, CO2H). Analysis of (C15H12N2O2) C, H, N.

Activation and coupling of the above acid gave bis [3- (6,9-dimethylphenazine-1-carboxamido) propyl] methylamine (65) as a light yellow solid (53%), mp 97-101 ° C (CH2Cl2 / n-hexane) ¹ H NMR (CDCl3) δ 2.02 (m, 4 H, 2xCH2CH2CH2), 2.34 (s, 3 H, NCH3), 2.60-2.68 (br m, 4 H, CH 2 N (CH 3) CH2), 2.68 (s, 6H, 2xArCH3), 2.78 (s, 6H, 2xArCH3), 3.70 (q, J = 6.6Hz, 4H, 2xCH2NH), 7.32- 7.40 (m, 4 H, H-7 and H-8), 7.86 (dd, J = 8.6, 7.2 Hz, 2 H, H-3), 8.28 (dd, J = 8.7, 1.5 Hz, 2 H, H-4), 8.90 (dd, J = 7.1, 1.5 Hz, 2 H, H-2) and 11.00 (br s, 2H, 2xCONH);

HRMS (FAB +) m / z calcd for C37H40N7O2 614.3243 (MH ⁺ ), found 614.3237. Analysis (C ₃₇ H ₄₀ N ₇ O ₂ O, 5H ₂ O) C, H, N.

Example 66: Preparation of compound 66 from Table I. A mixture of 5-chloro-2-methylaniline (8.63 g, 61.0 mmol), 2-bromo-3-nitrobenzoic acid (10.0 g, 41.0 mmol), CuCl (0.5 g), copper powder (0.1 g) in butane-2,3-diol (25 ml) and N-ethylmorpholine (15 ml) were stirred and heated for 18 hours at 70 ° C . The reaction mixture was diluted with 0.5 M NH4OH (500 mL) then filtered through Celite. The orange filtrate was slowly added to the stirred 2N HCl solution and the resulting yellow precipitate was collected by filtration, dried and recrystallized to give 2 - [(5-chloro-2-methyl) phenylamino] -3-benzoic acid as a light yellow crystalline solid (70% ), mp 228-230 ° C (EtOAc / n-hexane),

GB ¹ 193 669 B1 H NMR (CDCl3) δ 2.35 (s, 3 H, CH3), 6.79 (d, J = 2.1 Hz, 1 H, H-6 '), 6,96-7 .00 (m, 2H, H-4 'and H-5'), 7.15 (d, J = 8.0 Hz, 1H, H-3 '), 8.07 (dd, J = 8 , 1, 1.8 Hz, 1H, H-4 or H-6), 8.24 (dd, J = 7.9,

1.7 Hz, 1H, H-6 or H-4) and 9.51 (s, 1H, COOH). Analysis (C14H11ClN2O4) C, H, N.

A solution of 2 - [(5-chloro-2-methyl) phenylamino] -3-benzoic acid (3.59 g, 11.7 mmol) and NaBH4 (2.62 g, 68.8 mmol) in 2 M NaOH was heated to at boiling point for 8 hours. The reaction mixture was then cooled and acidified with AcOH to precipitate the crude phenazic acid. This solid was collected and recrystallised to give 6-chloro-9-metylofenazyno-1-carboxylic acid as mustard-yellow needles (45%), m.p. 255-257 ° C (acetone) ¹ H NMR [(CD3) 2SO] δ 2.86 (s, 3H, CH3), 7.90 (dd, J = 7.4, 1.1Hz, 2H, ArH), 8.11-8.18 (m, 2H, ArH ), 8.57-8.61 (m, 2H, ArH) and 14.52 (br s, 1H, COOH). Analysis (C14H9ClN2O2) C, H, N, Cl.

The above 6-chloro-9-methylphenazine-1-carboxylic acid was activated and coupled to give bis [(6-chloro-9-methylphenazine-1-carboxamido) propyl] methylamine (66) as a greenish yellow solid (84%), m.p. 200-202 ° C (CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 1.97 (quintet, J = 7.2 Hz, 4 H, 2xCH2CH2CH2), 2.31 (s, 3 H, NCH 3) , 2.59 (t, J - 7.1 Hz, 4H, CH2N (CH3) CH2), 2.76 (s, 6H, 2xArCH3), 3.69 (q, J = 6.7 Hz, 4 H, 2xCH2NH), 7.50 (dd, J = 7.6, 1.0 Hz, 2 H, H-8), 7.78 (d, J = 7.5 Hz, 2 H, H-7) , 7.93 (dd, J = 8.7, 7.2 Hz, 2 H, H-3), 8.41 (dd, J = 8.7, 1.5 Hz, 2 H, H-2) , 8.94 (dd, J = 7.1, 1.5 Hz, 2H, H-4), and 10.72 (br s, 2H, 2xCONH);

HRMS (FAB ⁺⁾ m / z calcd for C35H34 Cl2N7O2 ³⁵ 654.2151 (MH ^+), found 654.2159. Analysis (C ₃₅ H ₃₄ Cl ₂ N ₇ O ₂ O, 5H ₂ O) C, H, N.)

Example 67: Preparation of compound 67 of Table I. Activation and coupling of the known [Rewcastle et al. J. Med. Chem. 1987,30,843] 4-methylphenazine-1-carboxylic acid gave bis [(4-methylphenazine-1-carboxamido) propyl] methylamine (67) as a light yellow solid, (78%), mp 218-220 ° C ( CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 2.04 (quintet, J = 7.0 Hz, 2 H, 2xCH2CH2CH2), 2.38 (s, 3 H, NCH 3), 2.75 (t , J = 7.3Hz, 4H, CH2N (CH3) CH2), 2.90 (s, 6H, 2xCH3), 3.71 (q, J = 6.3Hz, 4H, 2xCH2NH), 7 , 58 (ddd, J = 8.6, 6.7, 1.3 Hz, 2H, ArH), 7.65 (ddd, J = 8.6, 6.6, 1.4 Hz, 2H, ArH), 7.70 (dd, J = 7.2, 1.0 Hz, 2H, ArH), 7.94 (dd, J = 8.6, 0.9Hz, 2H, ArH), 8 .00 (d, J = 8.7Hz, 2H, ArH), 8.77 (d, J = 7.3Hz, 2H, ArH)

10.88 (br s, 2H, 2xCONH).

HRMS (FAB ⁺ ) m / z calcd for C35H36N7O2 586.2930 (MH ⁺ ), found 586.2922. Analysis (C ₃₅ H ₃₆ N ₇ O / 2.5H ₂ O) C, H, N.

Example 68: Preparation of Compound 68 of Table I. Activation of 9-methylphenazine-1-carboxylic acid and coupling with N, N'-bis (3-aminopropyl) ethylenediamine gave bis [3- (9-methyl-phenazine-1) carboxamido) propyl] -1,2-ethylenediamine (68) as a gum, which was converted to the dihydrochloride salt (100), mp (MeOH) 276 ° C, ¹ H NMR (D 2 O) δ 2.07 (quintet, J = 6 , 7 Hz, 4H, 2xCH2), 2.82 (s, 6H, 2xArCH3), 3.17 (m, 4H, 2xCH2), 3.31 (br s, 4H, 2xCH2), 3.65 (t, J = 6.6 Hz, 4H, 2xCH2), 7.87 (m, 4H, 4xArH), 7.96-8.00 (m, 4H, 4xArH), 8.27-8, 30 (m, 2H, 2xArH), 8.60 (d, J = 7.2Hz, 2H, 2xArH).

HRMS (FAB); Calculated for C36H38N8O2 615.3196 Found: 615.3196.

Example 69: Preparation of 69 from Table I. Activation of 6,9-dimethylphenazine-1-carboxylic acid and coupling with triethylenetetramine gave bis [2- (6-9-dimethylphenazine-1-carboxamido) ethyl] -1,2 -ethylenediamine (69) (99%), m.p. (dihydrochloride with MeOH) 299 ° C (decomposition).

^1H NMR (CF3CO2D) δ 3.06 (s, 6 H, 2xCH3), 3.09 (s, 6 H, 2xCH3), 3.87 (br s, 4 H, 2xCH2), 3.91 (br s , 4H, 2xCH2), 4.27 (br s, 4H, 2xCH2), 8.20 (d, J = 7.3Hz, 2H, H-7 or H-8), 8.24 (d , J = 7.3 Hz,

H, H-7 or H-8), 8.43 (t, J = 8.1 Hz, 2 H, H-3), 8.96 (d, J = 8.8 Hz, 2 H, H- 4), 9.02 (d, J = 7.3Hz, 2H, H -2). Analysis (C36H40Cl2N8O2) C, H, N.

Example 70: Preparation of 70 from Table I. Activation of 9-methylphenazine-1-carboxylic acid and coupling with N, N'-bis (3-aminopropyl) butanediamine gave bis [2- (9-methylphenazine-1-carboxamido) propyl ] -1,4-butanediamine (70) (73%), mp (CH2Cl2 / hexane) 86-90,5 ° C, ¹ H NMR (CDCl3) δ 1.53 (quintet, J = 3.2 Hz, 4H, 2xCH2), 1.97 (quintet, J = 7.0Hz, 4H, CH2), 2.62 (t, J = 6.2Hz, 4H, 2xCH2), 2.79 (t, J = 7.0Hz, 4H, 2xCH2), 2.88 (s, 6H, 2xCH3), 3.74 (q, J = 6.6Hz, 4H, 2xCH2), 7.71-7, 78 (m, 4H, ArH), 7.93 (dd, J = 8.7, 7.2Hz, 2H, H-3), 8.08 (d, J = 7.9, 0.8 Hz, 2H, ArH), 8.34 (dd, J = 8.7, 1.5 Hz, 2H, H-4), 8.96 (dd, J = 7.1, 1.5 Hz, 2 H, H -2), 11.05 (t, J = 5.2 Hz, 2H, 2xCONH). Analysis (C ₃₈ H ₄₂ N ₈ O ₂ d, 5H ₂ O) C, H, N.

PL 193 669 B1

Example 71: Preparation of Compound 71 from Table I. Activation of 5-methylacridine-4-carboxylic acid and coupling with triethylenetetramine gave bis [3- (5-methylacridine-4-carboxamido) ethyl] -1,2-ethylenediamine (71) (76%), mp (CH2Cl2 / hexane) 167-170 ° C, ¹ H NMR (CDCl3) δ 2.08 (s, 6 H, 2xCH3), 2.85 (s, 4 H, 2xCH2 ), 2.99 (t, J = 6.2Hz, 4H, 2xCH2),

3.74 (q, J = 6.1 Hz, 4H, 2xCH2), 7.39 (dd, J = 8.4, 6.8 Hz, 2H, H-2), 7.57-7.61 ( m, 4H, H-6 and H-7),

7.75 (d, J = 8.7Hz, 2H, H-8), 8.02 (dd, J = 8.4, 1.5Hz, 2H, H-1), 8.68 (s, 2H, H-9), 8.91 (dd, J = 7.2,

I, 5 Hz, 2H, H-3), 11.81 (t, J = 5.5 Hz, 2H, 2xCONH). Analysis (C36H36N6O2) C, H, N.

Example 72: Preparation of 72 from Table I. Activation of acridine-4-carboxylic acid and coupling with triethylenetetramine gave bis [3- (acridine-4-carboxamido) ethyl] -1,2-ethylenediamine (72) (72% ), mp (CH2Cl2 / hexane) 170-171 ° C, ¹ H NMR (CDCl3) δ 2.91 (s, 8 H, 4xCH2), 3.53 (q, J = 5.4 Hz, 4 H, 2xCH2), 7.53 (t, J = 7.4Hz, 2H, ArH), 7.68 (dd, J = 8.3, 7.1Hz, 2H, ArH), 7.81-7 , 85 (m, 2H, ArH), 8.03 (d, J = 8.3Hz, 2H, ArH), 8.22 (d, J - 8.9Hz, 2H, ArH), 8 , 26 (dd, J = 8.5, 1.4 Hz, 2 H, ArH), 8.64 (dd, J = 7.1, 1.6 Hz, 2 H, H-3),

9.87 (s, 2H, H-9), 11.56 (t, J = 5.0Hz, 2H, 2xCONH). Analysis (C ₃₄ H ₃₂ N ₆ O ₂ ^ 2H ₂ O) C, H, N.

Example 73: Preparation of compound 73 of Table I. Activation of the known [Rewcastle et al.

J. Med. Chem. 1987, 30, 843] of 9-methylphenazine-1-carboxylic acid and subsequent coupling with N, N'-bis (2-aminoethyl) -1,3-propanediamine gave bis [(9-methylphenazine-1-carboxamido) ethyl] - 1,3-propanediamine (73) as a yellow solid (68%), m.p. 194-195 ° C (CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 1.73 (quintet, J = 6.9 Hz, 2H, CH2CH2CH2), 2.79 (t, J = 6.69Hz, 4H, 2xCH2),

2.88 (s, 6H, 2xArCH3), 2.97 (t, J = 6.2Hz, 4H, 2xCH2), 3.75 (q, J = 6.0Hz, 4H, 2xCH2), 7, 64-7.69 (m, 2H, ArH), 7.72 (dd, J = 8.6, 6.8Hz, 2H, ArH), 7.93 (dd, J = 8.7, 7 , 2 Hz, 2 H, ArH), 8.04 (dd, J = 8.7, 0.9 Hz, 2 H, ArH), 8.33 (dd, J = 8.7, 1.5 Hz, 2 H, ArH), 8.96 (dd, J = 7.2, 1.5 Hz, 2 H, ArH) and 11.06 (br t, J - 5.3 Hz, 2 H, 2xCONH);

HRMS (FAB ⁺ ) m / z calcd for C35H37N8O2 601.3039 (MH ⁺ ), found 601.3043. Analysis (C3 ₅ H36N8O / 5H ₂ O) C, H, N.

Example 74: Preparation of Compound 74 from Table I. Activation of 6-chloro-9-methylphenazine-1-carboxylic acid as above followed by coupling with triethylenetetramine gave bis [2- (6-chloro-9-methylphenazine-1- carboxamido) ethyl] -1,2-ethylenediamine (74) as yellow solid, 6%, mp 301 ° C (decomposition) (HCl salt) (MeOH / EtOAc).

^1H NMR (CF3CO2D) δ 3.87 (br s, 4 H, 2xCH2NH), 4.04 (br s, 4 H, 2xCH2NH), 4.09 (s, 6 H, 2xCH3), 4.29 (br s, 4H, 2xCONHCH2), 8.25 (br d, J = 7.9Hz, 2H, ArH), 8.44 (br d, J = 7.7Hz, 2H, ArH), 8. 53 (br s, 2 H, ArH), 9.03 (br d, J = 8.7 Hz, 2 H, ArH) and 9.09 (br s, 2 H, ArH);

HRMS (FAB ⁺⁾ m / z calcd for C34H33 Cl2N8O2 ³⁵ 655.2104 (MH ^+), found 655.2075.

Example 74a: Preparation of Compound 74a from Table I. N, N'-dimethyl-N, N'-bis (cyanomethyl) ethylenediamine was synthesized by a literature method [Alcock et al., J. Chem Soc. Dalton Trans. 1987, 2643]. This compound (5.0 g, 100 mmol) was then hydrogenated over Raney Nickel in absolute EtOH saturated with dry ammonia for 5 days at 20 ° C (additional Raney Nickel added as needed). The catalyst was removed by filtration through celite and evaporation of solvents gave essentially pure N, N'-dimethyl-N, N'-bis (2-aminoethyl) ethylenediamine (4.6 g, 88%), ¹ H NMR (CDCl3) δ 2.24 (s, 6H, 2xCH3), 2.43 (br s, 4H, 2xCH2), 2.49 (s, 2H, 2xCH2), 2.73 (br s, 2H, 2xCH2), which was used directly.

9-Methylphenazine-1-carboxylic acid (1.0 g, 4.2 mmol), and CDI (1.36 g, 8.4 mmol) in DMF (10 mL) was stirred at 50-60 ° C for one hour. then cooled to 20 ° C. Dry benzene (20 ml) and Sephadex LH-20 (2 g) were added and the mixture was stirred at 20 ° C for 1 hour, then filtered on a Celite pad to remove the Sephadex. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in dry THF (15 ml) and cooled in ice salt. N, N'-dimethyl-N, N'-bis (2-aminoethyl) ethylenediamine (0.36 g,

2.1 mmol) and the mixture was stirred while it was warmed to 20 ° C. Water (50 ml) was added and the THF was evaporated under reduced pressure. The resulting precipitate was filtered and washed with an aqueous Na2CO3 solution (3x50 ml) and water, then dissolved in CH2Cl2 (100 ml) and dried (Na2SO4). Evaporation of the solvents gave the crude product which was chromatographed on silica gel, eluting with a gradient of 1-6% MeOH in CH2Cl2) to give 74a as an oil (1.1 g, 78 0), ¹ H NMR (CDCl3) δ 2.33 ( s, 6H, 2xNCH3), 2.63 (br s, 4H, CH3NCH2CH2NCH3), 2.74 (t, J = 6.5Hz, 4H, CONHCH2CH2), 2.83 (s, 6H, 2xArCH3 ), 3.73 (q, J = 6.2Hz, 4H, 2xCONHCH2), 7.61 (d, J =

PL 193 669 B1

6.7 Hz, 2 H, H-8), 7.68 (dd, J = 8.7, 6.8 Hz, 2 H, H-7), 7.89 (dd, J = 8.7, 7, 2 Hz, 2H, H-3), 7.98 (d, J =

8.7 Hz, 2H, H-6), 8.26 (dd, J = 8., 1.5 Hz, 2H, H-4), 8.89 (dd, J - 7.0, 1.5 Hz, 2H, H -2), 10.85 (t, J =

5.2 Hz, 2H, 2xOONH).

Example 75: Preparation of Compound 75 from Table I. N- (t-butoxycarbonyl) -3,3'-diamino-N-methyldipropylamine was prepared as described [Huang, TL, Dredar, SA, Manneh, VA, Blankenship, JW , Fries, DS, J. Med. Ohem., 1992, 35, 2414-2418]. Di-t-butyl dicarbonate solution (2.51 g

11.5 mmol) in THF (15 ml) was added over 1.5 hours to a solution of 3,3'-diamino-N-methyldipropylamine (5.00 g, 34.4 mmol) in THF (15 ml) which was kept at temperature. 0 ° 0 (ice / water). The reaction mixture was stirred for a further 18 h at room temperature, then the solvent was removed under reduced pressure and the resulting residue was partitioned between Na0l (saturated) (100 ml) and OH20l2 (200 ml). The OH2012 layer was washed with more NaOl solution (100 mL) then dried (Na2SO4) and the solvent removed in vacuo to yield N- (t-butoxycarbonyl) -3,3'-diamino-N-methyldipropylamine (2.58 g, 46 %) as a clear, viscous oil.

¹ H NMR (0D0l3) δ 1.44 [br s, 9 H, 0 (0H3) 3], 1.58-1.67 (m, 6 H, 2x0H20H20H2 and NH2), 2.22 (s, 3 H , NOH3), 2.34-2.40 (m, 4H, 2xOH2NOH3), 2.74 (t, J = 6.9Hz, 2H, OH2NH2), 3.12-3.21 (br m, 2H, OH2NHBO0) and 5.37 (br s, 1H, NHBO0).

Phenazine-i-carboxylic acid (494 mg, 2.24 mmol) was prepared by a literature method [Rewcastle, GW, Denny, WA, Baguley, B.0., J. Med. Ohem., 1987, 30, 843-857], and was further reacted with ODI (544 mg, 3.36 mmol) in dry DMF (15 mL) for 2.5 hours at 30 ° 0. The DMF was removed under reduced pressure and the resulting yellow solid was dissolved in a mixture of petroleum ether and OH2012 (40 mL, 3: 1). Upon cooling, the imidazolide crystallized out and this crude material was used in the following coupling reaction. The crude imidazolide was suspended in THF (20 mL), cooled to 0 ° 0 (ice / water), then a THF solution (20 mL) of the above N- (t-butoxycarbonyl) -3,3'-diamino-N- was added. methyldipropylamine (659 mg, 2.69 mmol). The reaction mixture was allowed to stir for a further 2 hours at 0 ° 0, then the solvent was removed under reduced pressure and the resulting yellow oil was partitioned between OH20I2 (200 ml) and 1M (Na2O3) (200 ml). The OH2012 layer was dried with Na2SO4, the solvent was removed in vacuo and the resulting yellow-green oil was purified by alumina chromatography (0.25% MeOH in OH2012) to afford N-1- (3- {N-methyl-N- [N- (t-butoxycarbonyl) -3-aminopropyl]} aminopropyl) -fenazyno-1-carboxamide (992 mg, 980) as a yellow-green oil, which was used directly. ^1H NMR (0D0l3) δ 1.41 (br s, 9 H, O (OH3) 3), 1.44 (br s, 2H, OH20H20H2NHBO0), 1.95-2.04 (m, 2H, OH20H20H2NHOAr), 2.18 (s, 3H, NOH3), 2.46 (t, J = 6.7Hz, 2H, OH2H20H2NHBO0), 2.56 (t, J = 7.2Hz, 2H, OH20H20H2NHOAr), 3.20 (m, 2H, OH2NHBO0), 3.74 (q, J = 6.2Hz, 2H, OH2NHOAr), 5.45 (br s, 1H, NHBOO), 7.89-8.00 (m, 3H, ArH), 8, 22-8.26 (m, 1H, ArH), 8.28-8.32 (m, 1H, ArH), 8.40 (dd, J = 8.7, 1.5Hz, 1H, ArH), 9.02 (dd, J = 7.1, 1.5 Hz, 1H, ArH) and 11.03 (br s, 1H, ONH).

To a solution of the above protected BO0 amine (545 mg, 1.21 mmol) in OH2O12 (8 mL), was added trifluoroacetic acid (8 mL). This mixture was stirred at room temperature for 2 hours at which point the reaction was complete to TL0. All solvents were removed under reduced pressure and the oily residue was partitioned between OH20I2 (100 ml) and 1 M (Na2O3) (100 ml). The aqueous layer was extracted with additional OH20I2 (4x100 mL) and all the OH20I2 extracts were combined and dried with Na2SO4. The solvent was removed under reduced pressure to give N-1- {3- [N-methyl-N- (3-aminopropyl)] aminopropyl} phenazine-1-carboxamide (392 mg, 92%) as a greenish yellow oil which was used directly. ¹ H NMR (0D0l3) δ 1.61-1.67 (m, 4 H, 0H20H20H2NH2), 2.00 (quintet, J = 7.1 Hz, 2 H, 0H20H20H2NH0OAr), 2.29 (s, 3 H , NOH3), 2.46 (t, J = 7.2Hz, 2H, OH20H20H2NH2), 2.59 (t, J = 7.2Hz, 2H, OH20H20H2NHOAr), 2.75 (t, J = 6.8 Hz, 2 H, OH2NH2), 3.72 (q, J = 6.5 Hz, 2H, OH2NHOAr), 7.89-7.99 (m, 3H, ArH), 8.22- 8.25 (m, 1H, ArH), 8.28-8.32 (m, 1H, ArH), 8.40 (dd, J = 8.6, 1.5Hz, 1H, ArH) , 9.01 (dd, J = 7.1, 1.5 Hz, 1H, ArH) and 11.01 (br s, 1H, ONH).

Known [Atwell, G.J., Rewcastle, G.W., Baguley, B.0., Denny, W.A., J. Med. Ohem., 1987, 30, 664-669] acridine-4-carboxylic acid (274 mg, 1.23 mmol) was reacted with ODI (300 mg, 1.85 mmol) to give the imidazolide which was isolated as above. The imidazolide was suspended in THF (15 mL), the suspension was cooled to 0 ° 0 (ice / water), then a solution of the above amine (392 mg, 1.12 mmol) in THF (10 mL) was slowly added. The reaction mixture was stirred for 2 hours

At 0 ° C, then 18 hours at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 mL) and 1 M (Na2CO3) (100 mL). The CH2Cl2 layer was dried with Na2SO4, solvent removed in vacuo to yield an orange solid which was purified by chromatography on alumina (0.5% MeOH in CH2Cl2 as eluent) and silica (1% MeOH and 0.25% triethylamine in CH2Cl2 as eluent) ) to give N-1- {3 - [{3 - [(axidinyl-4-carbonyl) amino] propyl} (methyl) amino] propyl} phenazine-1-carboxamide (75) (as a pale yellow solid; mp 171 -173 ° C (CH2Cl2 / n-hexane), ¹ H NMR (CDCl3) δ 1.88 (quintet, J = 5.6 Hz, 2 H, CH2CH2CH2), 2.02 (quintet, J = 6.0 Hz , CH2CH2CH2), 2.38 (s, 3H, NCH3), 2.65-2.70 (m, 4H, 2xCH2NCH3), 3.62-3.68 (m, 2H, CH2NHCO),

3.76 (q, J = 6.5 Hz, 2H, CH2NHCO), 7.11 (t, J = 7.7 Hz, 1H, ArH), 7.22-7.29 (m, 1H , ArH), 7.36 (d, J = 8.3 Hz, 1H, ArH), 7.65 (ddd, J = 8.3, 6.9, 1.5 Hz, 1H, ArH), 7.85-7.93 (m, 3H, ArH), 8.00 (dd, J = 7.5, 0.9Hz, 1H, ArH), 8.09-8.13 (m, 1 H, ArH), 8.23-8.27 (m, 1H, ArH), 8.36 (dd, J = 8.6, 1.5Hz, 1H, ArH), 8.42 (d, J = 8.1 Hz, 1H, ArH), 8.53 (dd, J = 8.0, 1.2 Hz, 1H, ArH), 8.88 (dd, J = 7.2, 1, 5 Hz, 1H, ArH), 9.15 (s, 1H, H-9), 11.03 [br s, 1H, NH (phenazine)] and 12.55 [br s, 1H, NH (acridine)]. Analysis (C ₃₄ H ₃₂ N ₆ O / 2H ₂ O) C, H, N.

Example 76: Preparation of compound 76 of Table I by the method of Scheme 3. Coupling activation of 9-methylphenazine-1-carboxylic acid [Rewcastle, G.W., Denny, W.A., Baguley, B.C., J. Med. Chem., 1987, 30, 843-857] from N- (t-butoxycarbonyl) -3,3'-diamino-N-methyldipropylamine as in Example 75 gave N-1- (3- {N-methyl-N- [ N- (t-butoxycarbonyl) -3-aminopropyl]} aminopropyl) -9-methylphenazine-1-carboxamide as yellow green oil (89%) which was used directly.

¹ H NMR (CDCl3) δ 1.41 (br s, 9 H, C (CH3) 3), 1.65 (quintet, J = 6.6 Hz, 2 H, CH2CH2CH2NHBOC), 1.98 (quintet, J = 7.2Hz, 2H, CH2CH2CH2NHCOAr), 2.24 (s, 3H, NCH3), 2.42 (t, J = 6.7 Hz, 2H, CH2CH2CH2NHBOC), 2.53 (t, J = 7.3Hz, 2H, CH2CH2CH2NHCOAr), 2.94 (s, 3H, ArCH3), 3.12-3.23 (br s, 2H, CH2NHBOC), 3.73 (q, J = 6 , 7Hz, 2H, CH2NHCOAr), 5.39 (br s, 1H, NHBOC), 7.77 (dt, J = 6.5, 1.1Hz, 1H, ArH), 7.81 ( dd, J = 8.5, 6.8 Hz, 1H, ArH), 7.97 (dd, J = 8.7, 7.2Hz, 1H, ArH), 8.14 (d, J - 8.4Hz, 1H, ArH), 8.39 (dd, J = 8.6, 1.5Hz, 1H, ArH), 9.02 (dd, J = 7.2, 1.5Hz , 1H, ArH) and 11.13 (br t, J = 5.2Hz, 1H, CONH).

Deprotection of the above BOC protected amine as in Example 75 gave N-1- {3- [N-methyl-N- (3-aminopropyl)] aminopropyl} -9-methylphenazine-1-carboxamide as a green yellow oil, (85%). which was used directly.

¹ H NMR (CDCl3) δ 1.62 (quintet, J = 7.0 Hz, 2 H, CH2CH2CH2NH2), 1.98 (quintet, J = 7.3 Hz,

H, CH2CH2CH2NHCOAr), 2.26 (s, 3H, NCH3), 2.43 (t, J = 7.2Hz, 2H, CH2CH2CH2NH2), 2.53 (t, J =

7.3Hz, 2H, CH2CH2CH2NHCOAr), 2.75 (m, 2H, CH2NH2), 2.93 (s, 3H, ArCH3), 3.73 (q, J = 6.7Hz, 2H , CH2NHCOAr), 7.76 (dt, J = 6.7, 1.3 Hz, 1H, ArH), 7.81 (dd, J = 8.4, 6.9Hz, 1H, ArH), 7.97 (dd, J = 8.6, 7.1 Hz, 1H, ArH), 8.13 (dd, J = 8.7, 1.0 Hz, 1H, ArH), 8.38 ( dd, J = 8.7, 1.5 Hz, 1H, ArH), 9.00 (dd, J = 7.1, 1.5 Hz, 1H, ArH) and 11.11 (br s, 1 H, CONH).

5-methylacridine-4-carboxylic acid activation and coupling [Atwell, G.J., Rewcastle, G.W., Baguley, B.C., Denny, W.A., J. Med. Chem., 1987, 30, 664-669] with the above deprotected amine as in Example 75 gave N-1- {3 - [{3 - [(5-methylaxidinyl-4-carbonyl) amino] propyl} (methyl) amino] -propyl} -9-methylphenazine-1-carboxamide (76) as a pale yellow solid (66%), mp 116-121 ° C (CH2Cl2 / n-hexane).

¹ H NMR (CDCl3) δ 1.94-2.02 (m, 4 H, 2xCH2CH2CH2), 2.32 (s, 3 H, NCH 3), 2,58-2,63 (m, 4 H, 2xCH2NCH3) , 2.73 (s, 3H, ArCH3), 2.80 (s, 3H, ArCH3), 3.66-3.74 (m, 4H, 2xCH2NHCO), 7.31 (dd, J = 8 , 4, 6.8Hz, 1H, ArH), 7.52 (m, 2H, ArH), 7.59 (dd, J = 8.2, 7.2Hz, 1H, ArH), 7 , 63-7.69 (m, 2H, ArH), 7.90 (dd, J = 8.7, 7.2Hz, 1H, ArH), 7.95-8.00 (m, 2H , ArH), 8.28 (dd, J = 8.7, 1.5 Hz, 1H, ArH), 8.61 (s, 1H, H-9), 8.90-8.95 (m , 2H, ArH), 10.87 [br s, 1H, NH (phenazine)] and 11.78 [br s, 1H, NH (acridine)].

Analysis for N-1- {3 - [(3 - [(5-methylaxidinyl-4-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide (76) Analysis (C ₃₉ H ₃₆ N ₆ O / H ₂ O) C, H, N.

Example 77: Preparation of compound 77 of Table 1 by the method of Scheme 3. Activation and coupling of phenazine-1-carboxylic acid [Rewcastle, G.W., Denny, W.A., Baguley, B.C., J. Med. Chem., 1987, 30, 843-857] with N-1- {3- [N-methyl-N- (3-aminopropyl)] aminopropyl} -9-methylphenazine-1-carboxamide [for preparation see example 76] as above gave N-1- {3 - [{3 - [(phenazinylPL 193 669 B1

-1-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide (77) as yellow solid, 77%, mp 120 ° C (decomposition) (CH2Cl2 / n-hexane ).

¹ H NMR (CDCl3) δ 1.96-2.07 (m, 4 H, 2xCH2CH2CH2), 2.36 (s, 3 H, NCH3), 2.65-2.73 (m, 7 H, 2 x CH2NCH3 and ArCH3), 3.68-3.78 (m, 4H, 2x CH2NHCO), 7.47 (dt, J = 6.9, 1.1Hz, 1H, ArH), 7.57 (ddd, J = 8.7, 6.6, 1.2 Hz, 1H, ArH), 7.63 (dd, J = 8.7, 6.8 Hz, 1H, ArH), 7.71 (ddd, J = 8.7, 6.7,

1.5Hz, 1H, ArH), 7.87 (dd, J = 8.7, 7.2Hz, 1H, ArH), 7.90 (dd, J = 8.6, 7.1Hz , 1H, ArH), 7.94 (d, J = 9.2Hz, 1H, ArH), 8.00 (d, J = 8.6Hz, 1H, ArH), 8.08 (d , J = 8.5Hz, 1H, ArH), 8.21 (dd, J = 8.7,

1.5Hz, 1H, ArH), 8.31 (dd, J = 8.7, 1.5Hz, 1H, ArH), 8.89 (dd, J = 7.1, 1.5Hz , 1H, ArH), 8.92 (dd, J = 7.2, 1.5Hz, 1H, ArH) and 10.87 (br s, 2H, 2x NH).

Analysis for N-1- {3 - [{3 - [(phenazinyl-1-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide (77) Analysis (C ₃₄ H ₃₃ N ₇ O / H ₂ O) C, H, N.

Example 78: Preparation of compound 78 of Table I by the method of Scheme 3. Triethylenetetramine was reacted with di-t-butyl dicarbonate according to the method of Blagbrough et al. (Pharm. Sciences, 1997, in press; personal information) to yield, after purification by column chromatography (20% MeOH in CH2Cl2 as eluent), N-aminoethyl-N, N'-bis (t-butoxycarbonyl) -N- [ (Nt-butoxycarbonyl) aminoethyl] ethylenediamine as a pale yellow high viscosity oil (59%).

¹ H NMR (CDCl3) δ 1.39-1.50 [m, 29 H, 3xC (CH3) 3, NH2], 3,00-3,62 (m, 12 H, 6xCH2), 4.45 (br s, 1H, NHBOC).

5-Methylacridine-4-carboxylic acid (1.00 g, 4.23 mmol) was reacted with CDI (1.02 g, 6.33 mmol) to give the imidazolide as described above. The imidazolide was suspended in THF (80 ml) at room temperature and a solution of the above amine (2.04 g, 4.65 mmol) in THF (20 ml) was slowly added. The reaction mixture was then stirred for 18 hours at 20 ° C. The THF was removed under reduced pressure and the resulting yellow solid was partitioned between CH2Cl2 (200 mL) and 1 M Na2CO3 (200 mL). The CH2Cl2 layer was dried with Na2SO4 and the solvent removed in vacuo to yield a yellow oil which was purified by alumina column chromatography (0.5% MeOH in CH2Cl2 as eluent) to provide the triBOC analog N-1- [2- (N- {2 - [N- (2-Aminoethyl)] aminoethyl}) aminoethyl] -5-methylacridine-4-carboxamide as yellow foam (1.41 g, 51%).

¹ H NMR (CDCl3) δ 1.46 [m, 30 H, 3xC (CH3) 3, ArCH 3], 3,13-3,65 (m, 12 H, 6xCH2), 4.43 (br s, 1 H, , NHBOC), 7.48-7.55 (m, 1H, ArH), 7.64-7.74 (m, 2H, ArH), 7.88-7.94 (m, 1H, ArH ), 8.12-8.19 (m, 1H, ArH), 8.85-8.90 (m, 1H, ArH), 8.93-9.00 (m, 1H, ArH), 12.23 (br s, 1H, NH).

Trifluoroacetic acid (10 mL) was added to a solution of the above tri-BOC amide (1.00 g, 1.52 mmol) in CH2Cl2 (10 mL). The mixture was stirred at 20 ° C for 2 hours at which time the reaction was complete by TLC. All solvents were removed under reduced pressure and the oily residue was partitioned between CHCl3 (100 mL) and saturated Na2CO3 (20 mL). The aqueous layer was then extracted with additional CHCl3 (1x 100 mL) and all CHCl3 extracts were combined and dried with Na2SO4. The solvent was removed under reduced pressure to give N-1- [2- (N- {2- [N- (2-aminoethyl)] aminoethyl}) aminoethyl] -5-methylacridine-4-carboxamide (533 mg, 98%) as yellow oil.

¹ H NMR (CDCl3) δ 2.58-2.68 (m, 2 H, CH2), 2.70-2.76 (m, 4 H, 2xCH2), 2,82-2,86 (m, 2 H, CH2), 2.93 (s, 3H, ArCH3), 3.03-3.07 (m, 2H, CH2), 3.82-3.88 (m, 2H, CH2), 7 , 49-7.55 (m, 1H, ArH), 7.657.75 (m, 2H, ArH), 7.89-7.94 (m, 1H, ArH), 8.13-8.18 (m, 1H, ArH), 8.88 (br d, J = 5.3Hz, 1H, ArH), 8.98 (td, J = 7.1, 1.5Hz, 1H, ArH ), 12.04 (br s, 1H, NH).

9-Methylphenazine-1-carboxylic acid (1.00 g, 4.20 mmol) was reacted with CDI (1.02 g, 6.30 mmol) to give the imidazolide which was isolated as above. This imidazolide was suspended in THF (20 mL), the suspension was cooled to 0 ° C (ice / water), then a solution of the above polyamine (529 mg, 1.48 mmol) in THF (20 mL) was slowly added. The reaction mixture was stirred for hours at 0 ° C, then 18 hours at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 mL) and 1 M Na2CO3 (100 mL). The CH2Cl2 layer was dried with Na2SO4 and the solvent removed in vacuo to yield a yellow solid (553 mg, 61%) which was purified by alumina column chromatography (2% MeOH in CH2Cl2 as eluent) to afford N-1- (2 - {[ 2 - ({2 - [(5-methylacridinyl-4-carbonyl) amino] ethyl} amino) ethyl] amino} ethyl) -9-methylphenazine-1-carboxamide (78) as a yellow solid.

¹ H NMR (CDCl3) δ 2.77 (s, 3 H, ArCH 3), 2.79 (s, 3 H, ArCH 3), 2,82-2,88 (m, 4 H, 2xCH2), 2.97 (t, J = 6.0Hz, 2H, CH2), 3.02 (t, J = 6.0Hz, 2H, CH2), 3.70 (q, J = 5.9Hz, 2H , CH2), 3.79 (q, J =

PL 193 669 B1

6.0Hz, 2H, CH2), 7.31 (dd, J = 8.4, 6.8Hz, 1H, ArH), 7.51-7.70 (m, 5H, ArH), 7.87 (sd, J = 8.5, 7.1

Hz, 1H, ArH), 7.91-7.96 (m, 2H, ArH), 8.26 (dd, J = 8.7, 1.5Hz, 1H, ArH), 8.57 [s, 1H, H-9 (acridine)], 8.85-8.91 (m, 2H, ArH), 10.83 [br t, J = 5.1 Hz, 1H, NH (phenazine )], 11.83 [br t, J = 5.4 Hz, 1H,

NH (acridine)].

Example 79: Preparation of Compound 79 of Table I by the method of Scheme 3. Ethylenediamine was alkylated with excess chloroacetonitrile according to the method of Overman and Burk [Bradshaw et al., Tetrahedron, 1992, 48, 4475], and the product was purified by filtration by filtration through flash silica pad (1% MeOH in CH2Cl2 as eluent) to give N, N'-bis (cyanomethyl) ethylenediamine as a yellow oil which solidified on cooling (88%), mp 41-42 ° C.

¹ H NMR (CDCl3) δ 1.58 (s, 2 H, 2xNH), 2.90 (s, 4 H, 2xCH2), 3.63 (s, 4H, 2xCH2).

The above diamine (3.00 g, 21.7 mmol) in a mixture of THF (90 mL), water (10 mL), and triethylamine (10 mL) was treated with di-t-butyl dicarbonate (19.0 g, 87.0 mmol) . All solvents were removed under reduced pressure and the resulting residue was partitioned between water (100 mL) and EtOAc (2x100 mL). The combined EtOAc layers were dried (Na2SO4), the solvent removed and the resulting pale brown solid was purified by flash chromatography on silica (50% EtOAc / PE as eluent) to afford N, N'-bis (t-butoxycarbonyl) -N, N'-bis (cyanomethyl) ethylenediamine as a white solid (6.59 g, 90%), m.p. 112-113 ° C (EtOAc / petroleum ether).

¹ H NMR (CDCl3) δ 1.50 [s, 18 H, 2xC (CH3) 3], 3.52 (s, 4 H, 2xCH2), 4.13 (br s, 4H, 2xCH2).

Hydrogenation of the above with W-7 Raney nickel according to literature procedure [Ravikumar, Syn. Commun., 1994, 24, 1767] gave N, N'-bis (aminoethyl) -N, N'-bis (t-butoxycarbonyl) ethylenediamine as a white solid (100%), mp 81-82 ° C.

¹ H NMR (CDCl3) δ 1.46 [s, 18 H, 2xC (CH3) 3], 1.57 (br s, 4 H, 2xNH2), 2.83 (br s, 4 H, 2xCH2), 3 . 30 (br m, 8H, 4xCH2).

The above diamine was reacted with ethyl trifluoroacetate according to the method of Blagbrough et al. (Pharm. Sciences, 1997, in press; personal information) to yield N-aminoethyl-N, N'-bis (t-butoxycarbonyl) -N '- [(N-trifluoroacetamido) aminoethyl] -ethylenediamine as clear oil (39% ).

¹ H NMR (CDCl3) δ 1.46 [s, 18 H, 2xC (CH3) 3], 1.95 (br s, 2H, NH2), 2.84-2.96 (m, 2 H, CH2 ), 3.20-3.48 (m, 10H, 5xCH2), 7.99, 8.21, 8.51 (all br s, total 1H, NH).

Phenazine-1-carboxylic acid (212 mg, 0.95 mmol) was reacted with CDI (230 mg, 1.42 mmol) to give the imidazolide which was isolated as above. The imidazolide was then suspended in THF (10 mL) and a THF solution (10 mL) of the above monotrifluoroacetamide (416 mg, 0.95 mmol) was slowly added to the solution. This mixture was allowed to stir at room temperature for 18 hours, then the solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 ml) and 1 M Na2CO3 (50 ml). The CH2Cl2 layer was then dried with Na2SO4 and the solvent removed in vacuo to yield a residue which was purified by alumina chromatography (0.5% MeOH in CH2Cl2 as eluent) to afford N-1- (2- [N'-t-butoxycarbonyl- N '- (2- {Nt-butoxycarbonyl-N- [2- (N-trifluoroacetamido) aminoethyl] aminoethyl)] aminoethyl} phenazine-1-carboxamide as yellow oil (558mg, 91%).

¹ H NMR (CDCl3) δ 1.39 [br s, 9 H, C (CH3) 3], 1.43 [br s, 9 H, C (CH3) 3], 3,31-3,68 (m , 10H, 5xCH2), 3.82-3.8.9 (m, 2H, CH2), 7.90-8.44 [m, 7H, 6xArH, NHC (O) CF3], 8.99 (br s, 1H, ArH). 11.13 (br s, 1H, CONH).

A solution of the above trifluoroacetamide (548 mg, 0.85 mmol) in a mixture of MeOH (30 mL) and H2O (20 mL) was treated with K2CO3 (584 mg, 4.23 mmol). This mixture was stirred and refluxed for 2 hours, then at room temperature for 18 hours. Pure conversion of the trifluoroacetamide to the free amine was observed by TLC. The MeOH was removed under reduced pressure, then saturated Na2CO3 (20 mL) was added to the residue and this aqueous portion was extracted with CHCl3 (2x50 mL). The combined CHCl3 portions were dried with Na2SO4, then the solvent was removed in vacuo to give N-1- [2- (N'-t-butoxycarbonyl-N '- {2- [N- (aminoethyl) -Nt-butoxycarbonyl] aminoethyl}) aminoethyl] phenazine-i-carboxamide (470 mg, 100%).

¹ H NMR (CDCl3) δ 1.38 [br s, 9 H, C (CH3) 3], 1.43 [br s, 9 H, C (CH3) 3], 2.78 (t, J = 6 , 5 Hz, 2H, NH2), 3.18-3.70 (m, 10H, 5xCH2), 3.81-3.90 (m, 2H, CH2), 7.89-8.00 ( m, 3H, ArH), 8.21-8.43 (m, 3H, ArH), 9.00 (br s, 1H, ArH), 11.08 (br s, 1H, CONH).

PL 193 669 B1

The acridine-4-carboxylic acid (192 mg, 0.86 mmol) was reacted with CDI (210 mg,

I, 29 mmol) to give the imidazolide which is isolated as above. The resulting imidazolide was then suspended in THF (20 mL) and a THF solution (10 mL) of the above amine (470 mg, 0.86 mmol) was added slowly to the stirred solution. This mixture was allowed to stir at room temperature for 18 hours, then the solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (100 ml) and 1 M Na2CO3 (50 ml). The CH2Cl2 layer was dried with Na2SO4 and the solvent removed in vacuo to leave a residue which was purified by alumina column chromatography (0.5% MeOH in CH2Cl2 as eluent) to afford N-1- (2 - {[2 - ({2- [(acridinyl-4-carbonyl) amino] ethyl} -Nt-butoxycarbonylamino) ethyl] -N'-t-butoxycarbonylamino} ethyl) phenazine-1-carboxamide as yellow oil (568mg, 890).

¹ H NMR (CDCl3) δ 1.42 [br s, 9 H, C (CH3) 3], 1.46 [br s, 9 H, C (CH3) 3], 3,37-3,69 (m , 10H, 5xCH2), 3.81-3.89 (m, 2H, CH2), 7.09-7.15 (m, 1H, ArH), 7.25 (t, J = 7.4 Hz, 1H, ArH), 7.36 (d, J = 8.3Hz, 1H, ArH), 7.64 (t, J = 7.2Hz, 1H, ArH), 7.83- 7.97 (m, 4H, ArH), 8.11-8.27 (m, 3H, ArH), 8.318.45 (m, 2H, ArH), 8.53-8.61 (br s , 1H, ArH), 8.89-8.99 (br s, 1H, ArH), 11.10 (s, 1H, CONH (phenazine)], 12.52 [s, 1H, CONH ( acridine)].

HCl gas was bubbled through MeOH until the solution was strongly acidic when tested with paper. The above protected amine was dissolved in this solution (20 ml) and stirred at room temperature for 18 hours. MeOH was removed under reduced pressure and the residue was dissolved in saturated Na2CO3 (50 mL) which was then extracted with CHCl3 (13 x 50 mL). The combined CHCl3 extracts were dried with Na2SO4, then the solvent was removed in vacuo to give N-1- (2 - {[2 - ({2 - [(acridinyl-4-carbonyl) amino] ethyl} amino) ethyl] amino} ethyl) phenazine-1-carboxamide (79) as a yellow solid (159 mg, 96%) mp 173-176 ° C (CH2Cl2 / MeOH).

¹ H NMR (CDCl3) δ 2,83-2,96 (m, 6 H, 3xCH2), 3.07 (t, J = 5.9 Hz, 2 H, CH2), 3.46 (q, J = 5.3Hz, 2H, CH2), 3.80 (q, J = 5.8Hz, 2H, CH2), 7.01 (t, J = 7.8Hz, 1H, ArH), 7 , 25 (ddd, J = 8.1, 7.2, 0.9Hz, 1H, ArH), 7.32 (d, J = 8.2Hz, 1H, ArH), 7.55 (br s, 1H, ArH), 7.65 (ddd, J = 8.3, 7.0, 1.5Hz, 1H, ArH), 7.79-7.90 (m, 4H, ArH) , 8.12-8.16 (m, 2H, ArH), 8.26 (dd, J = 8.7, 1.5Hz, 1H, ArH), 8.39 (dd, J = 8, 1.1.3Hz, 1H, ArH), 8.43 (dd, J = 8.1, 1.4Hz, 1H, ArH), 8.89 (dd, J = 7.1, 1, 5 Hz, 1H, ArH),

II, 11 [s, 1H, CONH (phenazine)], 12.20 [s, 1H, CONH (acridine)].

Example 80: Biological Assays of Compounds of the Invention.

In vitro test

The in vitro cytotoxicity of compounds of the present invention was assessed in murine leukemia P388, the LLTC late passage mouse lung carcinoma line, and the wild type human leukemia line (Jurkat; JLC). Cells were grown as described by Finlay et al. in Oncol. Res. 1994, 6, 33-37 and Eur. J. Cancer 1996, 32A, 708-714, and growth inhibition of the sample was performed by culturing cells at 4 x 10 ³ (P388), 10 ³ (LLTC) and 3.75 x 10 ³ (Jurkat lines) per well in microculture plates ( 150 μl per well) for 3 (P388) or 4 days in the presence of drug. Cell growth was determined by uptake ^[3 H] TdR (P388) as described by Marshall et al. in J. Natl. Cancer Inst. 1992, 84, 340-345 or in the sulforhodamine assay as described by Skehan et al. in J. Natl. Cancer Inst. 1990, 82, 1107-1112. Independent trials were performed in duplicate and the coefficients of variation were 12% (P388), 12% (LLTC), and 6.3% (JLC).

T a b e l a II. The biological activity of selected compounds of formula (I) listed in Table I.

No IC50 values (nM) P388 LLTC JLc 1 2 3 4 6 <6 11 7 170 8 738 1540 9 1086 2543 10 620 167 345

PL 193 669 B1 cont. table II

1 2 3 4 11 32 87 12 8 33 13 10 7 28 14 15 39 114 15 76 17 58 16 27 twenty 52 17 59 13 66 18 49 17 69 19 165 380 twenty 322 223 21 370 73 275 22 1370 795 1640 23 1500 2079 2079 24 1630 1620 1300 26 twenty 147 27 138 36 99 28 190 <24 137 29 220 36 226 31 1293 141 250 33 56 81 110 34 320 209 473 35 260 81 93 36 140 18 102 38 520 119 137 41 151 209 42 74 300 43 600 64 195 44 83 274 45 142 175 46 24 thirty 47 2.2 4.8 51 500 1310 1250 52 120 172 53 8.8 14 54 44 8.5 16 55 2130 671 1550 56 972 183 760

PL 193 669 B1 cont. table II

1 2 3 4 57 35 3.2 11 58 _* 1.1 3.8 59 41 8.8 20.3 60 _* 5.0 13 61 435 48 208 62 204 12 74 63 12300 8370 2370 64 94 43.5 42.3 65 26 5.3 21.3 66 33 5.2 9.8 67 _* 17 85 68 _* 33.6 1.2 69 _* 3.9 0.55 70 _* 112 8.7 71 24 7.7 0.6 72 630 > 50 6.9 73 <6.2 1.2 0.24 74 39 10.5 0.6 75 _* 78 272 76 _* 1.8 8.8 77 _* 19 31

In vivo test

Selected compounds of general formula (I) also showed in vivo activity against subcutaneous colon tumor in mice. These data are illustrated in the appended Figure 1 for compounds 13 (at mg / kg) and 17 (at 90 mg / kg). In this trial, 38 colon tumors were grown subcutaneously with 1 mm ³ fragments implanted subcutaneously in one flank of anesthetized mice (pentobarbitone 90 mg / kg). Treatment was started when they reached about 4 mm in diameter (normally after 7 days). Mice were divided into groups of 5 for control and drug treatment, with average tumor volumes similar for each group. Drugs were dissolved in distilled water or 15% aqueous ethanol and injected at a volume of 0.01 ml per gram of body weight in divided doses of two equal injections given one hour apart. The mice were observed closely and weighed after 7 days to check for weight loss due to the drug. Mice were sacrificed when the average tumor size exceeded mm. The diameters were measured with tentacles three times a week and the tumor volumes were calculated as 0.52 * a ² * b, where a and b represent the major and minor axis of the tumor. The data were plotted on a semi-log plot (mean tumor volume versus time after treatment), and the time taken for the tumor to reach mean volume four times greater than before treatment was calculated. Hence, the tumor growth delay relative to the control mice was calculated.

Claims (9)

A compound which is a bis (acridinecarboxamide) or bis (phenazinecarboxamide) derivative of formula (I) Wherein each X, which may be the same or different on a given molecule, is -OH = or -N =; each of R1 to R4, which may be the same or different, is H, 01-04-alkyl, OH, NH2, 01-04-alkoxy, phenyl, phenyloxy, NHR, N (R) 2, wherein R is 01 -04-alkyl, OH3 or halogen; each of R5 and R6, which may be the same or different, is H or 01-04 alkyl; Z is (OH2) n, (OH2) nO (OH2) n, (OH2) nN (R7) (OH2) n, (OH2) nN (R7) (OH2) mN (R7) (OH2) n or (OH2) nN (OH20H2) 2N (OH2) n, (OH2) nONH (OH2) m or (OH2) nOONH (OH2) mNHOO (OH2) n, where R7 is H or 01-04-alkyl and nim, which may be or different, represent integers from 1 to 4; or a pharmaceutically acceptable acid addition salt thereof; except for compounds where each X is N, each of R1 to R6 is H, the carboxamide moiety is attached to the 1-position of each phenazine ring and Z is (OH2) 2NH (OH2) 2, (OH2) 3NH (OH2) 3, (OH2) 3N (OH20H2) 2N (OH2) 3, (OH2) 2NH- (OH2) 2NH (OH2) 2 or (OH2) 3NH (OH2) 2NH (OH2) 3. 2. A compound according to claim 1 which is a bis (acridinecarboxamide) derivative of formula (Ia): wherein each of R1 and R3 which are the same or different is 01-04-alkoxy, 01-04-alkyl or halogen, each of R2 and R4 which are the same or different is hydrogen, 01-04- alkoxy, 01-04 -alkyl or halogen and each of R5 and R6 is H; or a pharmaceutically acceptable salt thereof. 3. The compound according to p. 1, which is a bis (phenazinecarboxamide) derivative of formula (Ib): wherein each of R1 and R3 which are the same or different is 01-04-alkoxy, 01-04-alkyl or halogen, each of R2 and R4 which are the same or different is hydrogen, 01-04- alkoxy, 01-04 -alkyl or halogen and each of R5 and R6 is H; or a pharmaceutically acceptable salt thereof. 4. The compound according to p. 2 which is bis [(7-ethylacridine-4-carboxamido) propyl] methylamine; bis [(1-methylacridine-4-carboxamido) propyl] methylamine; bis [(1-chloroacridine-4-carboxamido) propyl] methylamine; bis [(2-methylacridine-4-carboxamido) propyl] methylamine; bis [(2-chloroacridine-4-carboxamido) propyl] methylamine; bis [(3-methylacridine-4-carboxamido) propyl] methylamine; bis [(5-methylacridine-4-carboxamido) propyl] methylamine; bis [(5-ethylacridine-4-carboxamido) propyl] methylamine; bis [(5-isopropylacridine-4-carboxamido) propyl] methylamine; bis [(5-phenylacridine-4-carboxamido) propyl] methylamine; bis [(5-methoxyacridine-4-carboxamido) propyl] methylamine; bis [(5-fluoroacridine-4-carboxamido) propyl] methylamine; Bis [(5-chloroacridine-4-carboxamido) propyl] methylamine; bis [(5-bromoacridine-4-carboxamido) propyl] methylamine; bis [(6-methoxyacridine-4-carboxamido) propyl] methylamine; bis [(6-fluoroacridine-4-carboxamido) propyl] methylamine; bis [(6-chloroacridine-4-carboxamido) propyl] methylamine; bis [(7-methylacridine-4-carboxamido) propyl] methylamine; bis [(7-isopropylacridine-4-carboxamido) propyl] methylamine; bis [(7-tert-butylacridine-4-carboxamido) propyl] methylamine; bis [(7-phenylacridine-4-carboxamido) propyl] methylamine; bis [(7-methoxyacridine-4-carboxamido) propyl] methylamine; bis [(7-fluoroacridine-4-carboxamido) propyl] methylamine; bis [(7-chloroacridine-4-carboxamido) propyl] methylamine; bis [(7-bromoacridine-4-carboxamido) propyl] methylamine; bis [(8-methylacridine-4-carboxamido) propyl] methylamine; bis [(8-chloroacridine-4-carboxamido) propyl] methylamine; bis [(acridine-2-carboxamido) propyl] methylamine; bis [(acridine-4-carboxamido) propyl] methylamine; bis [2- (acridine-4-carboxamido) ethyl] amine; bis [3- (acridine-4-carboxamido) propyl] amine; N ¹ , N4-bis [(acridine-4-carboxamido) propyl] piperazine; bis [(6-bromoacridine-4-carboxamido) propyl] methylamine; bis [(5-trifluoromethylacridine-4-carboxamido) propyl] methylamine; bis [(6-trifluoromethylacridine-4-carboxamido) propyl] methylamine; bis [(5,7-dimethylacridine-4-carboxamido) propyl] methylamine; bis [(6- (dimethylamino) acridine-4-carboxamido) propyl] methylamine; bis [(phenazine-1-carboxamido) propyl] methylamine; bis [(phenazine-2-carboxamido) propyl] methylamine; bis [(6-methylphenazine-1-carboxamido) propyl] methylamine; bis [(6-chlorophenazine-1-carboxamido) propyl] methylamine; bis [(7-methylphenazine-1-carboxamido) propyl] methylamine; bis [(7-methoxyphenazine-1-carboxamido) propyl] methylamine; bis [(7-chlorophenazine-1-carboxamido) propyl] methylamine; bis [(8-methylphenazine-1-carboxamido) propyl] methylamine; bis [(8-methoxyphenazine-1-carboxamido) propyl] methylamine; bis [(9-methylphenazine-1-carboxamido) propyl] methylamine; bis [(9-methylphenazine-1-carboxamido) propyl] -1,4-piperazine; bis [(9-methylphenazine-1-carboxamido) ethyl] -1,4-ethylenediamine; bis [(9-methoxyphenazine-1-carboxamido) propyl] methylamine; bis [(9-phenoxyphenazine-1-carboxamido) propyl] methylamine; bis [(9-fluorophenazine-1-carboxamido) propyl] methylamine; bis [(9-chlorophenazine-1-carboxamido) propyl] methylamine; bis [((9-dimethylamino) phenazine-1-carboxamido) propyl] methylamine; bis [3- (5- (dimethylamino) acridine-4-carboxamido) propyl] methylamine; bis [3- (7- (dimethylamino) acridine-4-carboxamido) propyl] methylamine; bis [3- (5,8-dimethylacridine-4-carboxamido) propyl] methylamine; bis [3- (1,5-dimethylacridine-4-carboxamido) propyl] methylamine; bis [3- (8-chloro-5-methylacridine-4-carboxamido) propyl] methylamine; bis [3- (1-chloro-5-methylacridine-4-carboxamido) propyl] methylamine; bis [2- (3-methylphenazine-1-carboxamido) propyl] methylamine; bis [(3-chlorophenazine-1-carboxamido) propyl] methylamine; bis [3- (2-chlorophenazine-1-carboxamido) propyl] methylamine; bis [3- (8-chlorophenazine-1-carboxamido) propyl] methylamine; bis [3- (6,9-dimethylphenazine-1-carboxamido) propyl] methylamine; bis [(6-chloro-9-methylphenazine-1-carboxamido) propyl] methylamine; bis [(4-methylphenazine-1-carboxamido) propyl] methylamine; bis [3 - (- 9-methylphenazine-1-carboxamido) propyl] -1,2-ethylenediamine; Bis [2- (6-9-dimethylphenazine-1-carboxamido) ethyl-1,2-ethylenediamine; bis [2- (9-methylphenazine-1-carboxamido) propyl-1,4-butanediamine; bis [3- (5-methylacridine-4-carboxamido) ethyl-1,2-ethylenediamine; bis [3- (acridine-4-carboxamido) ethyl-1,2-ethylenediamine; bis [(9-methylphenazine-1-carboxamido) ethyl] -1,3-propanediamine; bis [2- (6-chloro-9-methylphenazine-1-carboxamido) ethyl] -1,2-ethylenediamine; N-1- {3 - [{3 - [(acridinyl-4-carbonyl) amino] propyl} (methyl) amino] propyl} phenazine-1-carboxamide; N-1- {3 - [{3 - [(5-methylacridinyl-4-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide; N-1- {3 - [{3 - [(phenazinyl-1-carbonyl) amino] propyl} (methyl) amino] propyl} -9-methylphenazine-1-carboxamide; N-1- (2 - {[2 - ({2 - [(5-methylacridinyl-4-carbonyl) amino] ethyl} amino) ethyl] amino} ethyl) -9-methylphenazine-1-carboxamide; and N-1- (2 - {[2 - ({2 - [(acridinyl-4-carbonyl) amino] ethyl} amino) ethyl] amino} ethyl) phenazine-1-carboxamide. 5. A method of producing a compound as defined in claim 1 A process as claimed in claim 1, characterized in that two moles of acridinecarboxylic acid or 9-azaacridine carboxylic acid derivative of formula (II) are reacted: wherein R1, R2 and X are as defined in claim 1 1 and A is OH, Cl or N-imidazolyl, with one mole of the bis (amine) of formula (III): NHR5-Z-NHR6 (III) wherein R5, R6 and Z are as defined in claim 1, and if necessary, converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as defined in claim 1. 7. A compound of formula I as defined in claim 1 for use as a medical agent in therapy. 8. The compound of claim 1 7 for use as an anti-cancer agent. 9. The use of a compound of formula I as defined in claim 1 for the preparation of a medicament for the treatment of tumors.